List of Proteins

    Neuromuscular Disorders


    Muscular dystrophies

    Muscular dystrophies comprise a group of heterogeneous genetic myopathies that can cause repeated skeletal muscle degeneration and regeneration. The consequences of these molecular defects are apparent at the histological level, with a progressive degeneration of muscle fibres, ultimately resulting in tissue wasting. This becomes clinically evident in the form of weakness and limitation of motor capacity, which gradually increases in severity over time. PMID: 22450509, PMID: 16971897, PMID: 20041828, PMID: 18039094.

    The extracellular matrix (ECM) is a dynamic structure that provides cell support and anchoraging, it segregates tissues from one another and initiates signal transduction pathways. The ECM is primarily composed of glycoproteins, collagens and proteoglycans that are secreted and assembled locally into an organized network to which cells adhere via cell surface receptors. An ECM is already present in the mammalian embryo from the two-cell stage and is a component of the environment of all cell types, although the composition of the ECM and the spatial relationship between cells and the ECM differ between tissues.

    The interstitial matrix is present between cells, while the basement membrane is a thin sheet-like deposition of ECM that surrounds cells (e.g. muscle cells) or underlies cells (e.g. epithelial cells). The major components of the basement membranes are laminins, collagen type IV, nidogens and the heparan sulphate proteoglycan perlecan. PMID: 21989954, PMID: 19756756, PMID: 18219670.

    Changes in miRNA expression are associated with various skeletal muscle disorders, such as muscular dystrophies. Recent studies have uncovered a cadre of muscle-specific microRNAs that regulate diverse aspects of muscle function, including myoblast proliferation, differentiation, contractility and stress responsiveness. PMID: 19175696, PMID: 19278845, PMID: 21804598, PMID: 20195710, PMID: 18325627, PMID: 18222968, PMID: 21751030.

    Integrins form the major family of cell surface adhesion receptors, mediating both cell-cell and cell-matrix interactions. They are heterodimeric, transmembrane glycoproteins consisting of an alpha and a beta chain that are non-covalently associated. Moreover, they are signalling receptors involved in both outside-in and inside-out signalling. To date, 18 alpha and 8 beta chains have been identified. These combine in a restricted manner to form at least 24 different dimers. PMID: 1555235, PMID: 11572082.

    Duchenne Muscular Dystrophy (DMD)

    Becker Muscular Dystrophy (BMD)

    Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and limb girdle muscular dystrophies (LGMD) represent a significant proportion of paediatric and adult neuromuscular neurology practice. PMID: 11879882, PMID: 19531685.

    The skeletal muscle is the most abundant tissue in the body, and many neuromuscular disorders are multisystemic conditions. The development of effective therapies for neuromuscular disorders such as Duchenne muscular dystrophy (DMD) is hampered by considerable challenges. However, despite these barriers there has recently been substantial progress in the search for novel treatments, in particular, the use of antisense oligonucleotides. These molecules are designed to target RNA and modulate pre-mRNA splicing to restore functional protein isoforms. They can also directly inhibit the toxic effects of pathogenic RNAs, these promising approaches are now being tested in the clinic. PMID: 21804598, PMID: 22463740, PMID: 23387802, PMID: 21804598, PMID: 22137430

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the dystrophin gene. The phenotypic difference between DMD and BMD patients can mostly be explained by the type of mutations and the resulting consequences at the protein level. Generally, DMD patients exhibit an absence of dystrophin while BMD patients often harbour internally deleted but partially functional dystrophin proteins. DMD is a severe form of muscular dystrophy with onset around 3 years of age. It is characterized by progressive wasting of skeletal muscles, eventually resulting in cardiac and respiratory failure during the twenties age range. Patients usually lose independent ambulation in the second decade of life. BMD is similar to DMD in the distribution of muscle wasting and weakness, which is mainly proximal, but the course is more heterogeneous than in DMD. The onset of the disease is generally later during childhood compared to DMD. Some patients have no symptoms until later in life but others can be more affected. PMID: 19531685, PMID: 19892898, PMID: 16305275, PMID: 23117950.

    Among the various forms of DMD, X-linked is one of the most common (one in 3500 male births) and severe, with symptoms starting in early childhood. Muscle weakness is initially proximal and progressively leads to patients being confined to a wheelchair. Cardiac or respiratory failure, are the most frequent causes of death by the third decade of life. DMD is caused by mutations in the DMD gene encoding the dystrophin protein (2.4 Mb: the largest gene of the human genome), which stabilizes sarcolemma during muscle contractions, linking the cytoskeleton and extracellular matrix. PMID: 23387802, PMID: 20963914.

    Integrins consist of two non-covalently-associated subunits, alpha and beta. Integrin alpha 7 beta 1 is the main integrin isoform expressed in striated muscle. Several alternatively spliced isoforms of alpha 7 and beta 1 chains have been described and some are differentially expressed during muscle development and regeneration. PMID:10199978, PMID: 10403775.

    In skeletal muscle, alpha 7 beta 1 integrin interacts mainly with laminin-211 but it can also bind other laminin isoforms. Hence, the laminin-211–integrin alpha 7 beta 1 interaction creates an additional important link between the ECM and the cytoskeleton in skeletal muscle. A functional redundancy may exist between integrin alpha 7 beta 1 and the dystrophin-glycoprotein complex (DGC). Also, integrin alpha 7 beta 1 and dystroglycan contribute to force production in the muscle fibre. PMID: 19074617, PMID: 8626012, PMID: 11744715, PMID: 9354797, PMID: 16476707, PMID: 16684813.

    Laminin-111 is normally present in skeletal and cardiac muscles in mice and humans but only during embryonic development. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of alpha 7 integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for systemic delivery of extracellular matrix proteins a therapy for genetic diseases. PMID: 20683444, PMID: 19416897.

    Developmentally regulated expression and alternative splicing of the alpha 7 integrin chain are important for appropriate myogenic cell proliferation, adhesion, migration, and differentiation. Alleviation of muscular dystrophy by transgenic overexpression of the integrin in mdx/utrn−/− mice revealed the potential for using it as a therapy for muscular dystrophy. PMID: 18045857, PMID: 11257121, PMID: 9281377, PMID: 9004048.

    Studies performed in avian species have shown that beta 1 integrins are involved in cell migration from the somite and terminal differentiation of myoblasts into myotubes. In vitro studies in avian and rodent species demonstrated that the alpha 4 integrins, containing either the beta 1 or beta 7 subunit, and alpha v, alpha 5 beta 1, alpha 6 beta 1, and alpha 7 beta 1integrins play a major role in muscle differentiation. PMID: 3266744, PMID: 3115595.

    Integrins provide a similar link between the cytoskeleton and the extracellular matrix which make them strong candidate genes for unclassified forms of muscular dystrophies. Indeed, mice carrying an inactivated alpha 7 integrin gene develop a mild but progressive muscular dystrophy soon after birth. PMID: 9354797.

    The switch in the muscle cell environment from a fibronectin-rich matrix into a laminin-containing basement membrane with the onset of terminal differentiation has suggested the existence of a fine-tuned regulation of differentiation and matrix assembly via these two integrin receptors. PMID: 3758484.

    Guo and collaborators provided novel evidence that dystrophin and alpha 7 integrin act in concert to maintain muscle regeneration. PMID: 16476707.

    Various results have implicated alpha 7 beta 1 as the crucial receptor for myoblast migration, and its strong up-regulation in terminally differentiated myotubes, further suggesting a functional role in this process. PMID: 8567661, PMID: 8810334, PMID: 9281377, PMID: 23319059.

    Laminin receptors are thought to play pivotal roles for skeletal muscle function and integrity. All laminin isoforms detected in skeletal muscle are recognized by alpha 3 beta 1, alpha 6 beta 1, and alpha 7 beta 1. PMID: 11212297, PMID: 11278628, PMID: 10671376, PMID: 11744715, PMID: 19729483.

    Human patients have been identified with a primary integrin alpha 7 deficiency, resulting from a 21-bp insertion due either to a splice site mutation or deletions leading to frameshifts. This deficiency was apparent from birth with delayed motor milestones in the following years and was accordingly classified as congenital myopathy. PMID: 9590299, PMID: 16684813.

    Laminin beta 2 chain was similarly found in the skeletal muscle basement membranes in patients with Duchenne and Becker muscular dystrophy. PMID: 9273822.

    Recent evidence supports a role for miRNAs as integral components of the regulatory circuitry for muscle development. Current data on the roles of miRNAs in myogenesis have been obtained largely from studies on muscle-specific miR-1, miR-133 and miR-206. PMID: 17459947; PMID: 17008435; PMID: 17045567; PMID: 16380711; PMID: 15951802; PMID:16731620; PMID: 16923828; PMID: 17030984; PMID: 19175696; PMID: 18222968; PMID: 18325627.

    Muscle-specific miRNAs have been found and are significantly increased in serum of DMD models. Additionally, serum level of miR-1, -133a and -206 were not increased in steroid-treated dogs and did not show increase compared with non-treatment controls. PMID: 21479190, PMID: 21425469, PMID:20487562,

    Eisenberg and collaborators described 185 miRNAs that are up or down-regulated in 10 major muscular disorders in humans. Namely, DMD, BMD, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis, dermatomyositis, and inclusion body myositis. PMID: 17942673.

    The TGF-beta-miR-29 was identified as a novel regulatory axis during myoblasts conversion into myofibroblasts which constitutes a novel contributing route to muscle fibrogenesis of DMD but also implicates miR-29 replacement therapy as a promising treatment approach for DMD. PMID: 22434133.

    Interfering with miR-31 activity can provide an ameliorating strategy for those DMD therapies that are aimed at efficiently recovering dystrophin synthesis. PMID: 21212803.

    Limb Girdle Muscular Dystrophies (LGMD)

    The Limb-Girdle muscular dystrophies (LGMDs) are genotypically and phenotypically heterogeneous. As their name implies, these mypopathies are characterized by weakness of the proximal muscles in the upper and lower extremities. Onset can occur in childhood and the clinical presentation can mimic DMD, but onset more often occurs in late adolescence or early adulthood. Some of the most severe forms of LGMD are present at birth, and fall into the category of congenital muscular dystrophy (CMD). The heart is usually not affected, but patients with LGMD should be screened routinely because some will develop cardiomyopathy. Limb-girdle muscular dystrophies can either be autosomal dominant (single gene defect on a chromosome from either parent or one copy of a mutant gene and one normal gene, known as type 1 LGMD) or autosomal recessive (a defect or mutation on the gene from the chromosome of each parent is needed, known as type 2 LGMD). Type 2 LGMDs are more severe, with some resembling DMD in severity. Sixteen genetically different LGMDs have been identified, with a correspondingly wide range of phenotypes. PMID: 16305275, PMID: 9027854, PMID: 10196377, PMID: 12432825, PMID: 22856606.

    Using immunohistochemical methods, Patton and collaborators detected the distribution of all 10 known laminin chains (alpha1-5, beta1-3, gamma 1 and gamma 2) in skeletal muscles from patients with Duchenne, congenital, limb girdle, or Emery-Dreifuss muscular dystrophies. PMID: 10545049.

    LAMA2 mutations were identified in all patients with LGMD. The amount of laminin alpha 2 protein in the muscle biopsies ranged from trace to about 50% compared with controls. PMID: 21953594.

    Alterations in the nuclear lamina caused by mutations in lamin A/C, sarcomeric changes in titin, telethonin or myotilin at the Z-disc, and subtle changes in the extracellular matrix proteins laminin alpha 2 or collagen VI can all lead to a limb girdle muscular dystrophy phenotype. However, the specific pathological mechanisms remain obscure. The most consistent protein abnormality found in muscle biopsies was a reduction of laminin alpha 2 immunolabeling, either on muscle sections or immunoblotting alone. PMID: 15043707, PMID: 12707425, PMID: 11077661, PMID: 10679962, PMID: 9829280, PMID: 9259292.

    Reduced laminin beta 1 chain immunoreactivity may potentially serve as a marker for defining subsets of individuals with LGMD, in particular those with slowly progressive, adult-onset pelvifemoral presentation. PMID: 9400354.

    Congenital Muscular Dystrophy (CMD)

    Congenital muscular dystrophies are a class of relatively rare conditions that appear in infancy. The typical CMD cases are often those associated with disturbances in the central nervous system. A common form of CMD is associated with a protein in the dystrophin-associated protein complex (DAPC). Laminin is a component of the ECM that binds to dystroglycan in the DAPC. The alpha 2-chain of laminin, also known as merosin, is absent or depleted in this merosin-deficient CMD. Children with CMD have marked weakness and never acquire the ability to walk independently. The muscle weakness is usually not progressive, and life expectancy is almost normal. There is a slight increase in incidence of seizures and mental retardation in children lacking merosin. PMID: 11584042,PMID: 22172424, PMID: 16969582, PMID: 11369186.

    Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-2 is required for the formation of heterotrimeric laminin-211 (i.e., alpha 2, beta 1, and gammab1) and laminin-221 (i.e., alpha 2, beta 2, and gamma 1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (i.e., alpha 1, beta 1, and gamma 1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development, in laminin-2-deficient muscle but is absent from adult skeletal muscle. PMID: 11212297, PMID: 10639486, PMID: 9882526, PMID: 11969289, PMID: 9758133, PMID: 9396756.

    Laminin-221 is enriched at neuromuscular junctions and promotes efficient neurotransmission. PMID: 11969289.

    The loss of laminin-211/221 in MDC1A patients and mouse models results in poor myofibre adhesion, increased sarcolemmal fragility and sensitivity to apoptosis. Defective muscle regeneration and myofibre loss are also observed in laminin-2-deficient myofibres indicating that the laminin composition in the extracellular matrix plays a critical role in muscle maintenance. PMID: 10616210, PMID: 8830776, PMID: 19086074, PMID: 9312189, PMID: 15923403, PMID: 17389231, PMID: 19074617.

    Furthermore, mutations within the laminin alpha 2 chain result in severe forms of CMD both in human and the corresponding mouse model dy/dy. PMID: 7874173, PMID: 8910357, PMID: 7550355, PMID: 9390664.

    Facioscapulohumeral Muscular Dystrophy (FSHD):

    Emery-Dreifuss Muscular Dystrophy (EDMD):

    Oculopharyngeal Muscular Dystrophy (OPMD):

    Myotonic Dystrophy Types 1 (DM1) and 2 (DM2):

    After DMD and LGMDs, facioscapulohumeral muscular dystrophy (FSHD) is the third most commonly inherited muscle disease, affecting approximately 1 in 20,000 people in the United States. It is an autosomal dominant disorder with a variable age of onset, but it is usually first detected in early adolescence. As suggested by its name, FSHD is characterized by weakness in muscles of the face and proximal upper extremities, including those muscles that stabilize the scapula. This muscle weakness results in winging and anterior tilting of the scapula. Although extraocular muscles are not affected, weakness in muscles around the eye (i.e., obicularis oculi) may be evident. For example, when patients sleep with their eyes slightly open, a symptom that may manifest itself before other symptoms develop. There is also difficulty in whistling or blowing (e.g., blowing out candles). Distal extremity muscles can also be affected and the weakness is often asymmetric. There is a wide range of clinical severity overall, with symptoms that can include cardiac, cognitive, visual, and auditory impairments. Progression of FSHD is usually slow, these patients have a near-normal life expectancy. PMID: 1745341, PMID: 9633729, PMID: 16305275, PMID: 21734574, PMID: 21484336.

    FSHD diagnosis can be distinguished from DMD, based on the lack of dysregulation of miRNAs-381 and -382 found in FSHD patients. Similarly, nearly all of the LGMD myopathies have a significant up-regulation of miRNAs-100, -103, -107; whereas DMD patients do not. PMID: 17942673.

    Emery-Dreifuss muscular dystrophy (EDMD) is inherited in an X-linked or autosomal manner. X-linked EDMD is caused by mutations in EMD, which encodes an integral protein of the nuclear envelope inner membrane called emerin. Autosomally inherited EDMD is caused by mutations in LMNA, which encodes A-type nuclear lamins, intermediate filament proteins associated with inner nuclear membrane. This disorder is defined by early contractures of the Achilles tendon, spine, and elbows. EDMD is also distinctive for its association with defects of the cardiac conduction system that can result in sudden death. PMID: 21496632, PMID: 17217858, PMID: 16305275.

    Recently, a miRNA modulation in the serum of five mouse models was identified. Mouse models for five striated muscle pathologies were investigated: DMD, EDMD, limb-girdle muscular dystrophy type 2D (LGMD2D), limb-girdle muscular dystrophy type 2C (LGMD2C), and hypertrophic cardiomyopathy (HCM). miRNA modulation was identified in the serum of all five mouse models. The most highly dysregulated serum miRNAs were found to be commonly up-regulated in DMD, LGMD2D and LGMD2C mouse models, which all exhibited massive destruction of striated muscle tissues. PMID: 23418438.

    Oculopharyngeal Muscular Dystrophy (OPMD) is an autosomal dominant disorder that is characterized by progressive eyelid ptosis and progressive dysphagia, followed by involvement of other muscles of the head and neck, and eventually proximal limb weakness. Extraocular muscles are usually spared, although not always. Onset occurs in late adulthood, and a clinical test that is sometimes used is timed-swallowing, which is 2 times slower in affected individuals. OPMD is caused by an abnormal number of GCG trinucleotide repeats in the PABPN1 gene that encodes the polyadenylate binding protein, nuclear 1 protein. PMID: 9765171, PMID: 9392011, PMID: 16305275, PMID: 11222452.

    Myotonic dystrophies are the most common form of MD in adults. Myotonic dystrophies are now recognized as genetically heterogeneous diseases, caused by 2 distinct mutations. Myotonic dystrophy types 1 (DM1) and 2 (DM2) are similar yet distinct autosomal-dominant disorders characterized by muscle weakness, myotonia, cataracts, and multiple organ involvement, including the brain. DM1 is caused by an expansion of a CTG trinucleotide repeat in the DMPK gene, which encodes the dystrophia myotonica protein kinase. PMID: 1546325, PMID: 1546326. DM2 is caused by an expansion of a CCTG repeat in intron 1 of gene ZNF9, which encodes zinc finger protein 9 on chromosome 3q. PMID: 15231584, PMID: 12970845, PMID: 11486088.

    Both DM1 and DM2 are inherited in an autosomal dominant fashion, and both affect multiple organ systems. One key difference between DM1 and DM2 is that a congenital form has been described for DM1 only. Although the 2 types can be clinically indistinguishable in some cases, DM2 is more likely to be associated with more proximal weakness (proximal myotonic myopathy) as opposed to the predominantly distal weakness seen in DM1. PMID: 17486579, PMID: 16305275, PMID: 17027856.

    Up-regulated miR-1 and miR-335 were found in DM1, whereas miR-29b and c, and miR-33 were down-regulated in DM1 biopsies compared to controls. Moreover, the cellular distribution of muscle specific miR-1, miR-133b and miR-206 was severely altered in DM1 skeletal muscles. MicroRNA dysregulation was likely functionally relevant since it impacted on the expression of the predicted miR-1, and miR-29 targets. The observed miRNA dysregulations and myslocalizations may contribute to DM1 pathogenetic mechanisms. PMID: 21169019.

    Inflammatory Myopathies

    Inflammatory myopathies, are the most common of the acquired muscle disorders, comprising of three major and distinct subsets: polymyositis, dermatomyositis and inclusion body myositis (PMID:1658649, PMID:20409756). In rats, immunization with laminin induces moderate to severe myositis (PMID:16141789).

    Laminin also partakes in nuclear disintegration and rimmed vacuole formation in myositis (PMID:19130741).

    MMPs have important physiological functions in maintenance of the integrity and homeostasis of muscle fibers as well as the extracellular matrix (PMID:14755482). MMP-2 and MMP-9, which promote the migration of lymphocytes through the extracellular matrix, are also overexpressed on muscle fibres and autoinvasive CD8-positive cells. MMP9 immunoreactivity in muscle fibres is a common feature of all inflammatory myopathies (PMID:11157561, PMID:10636127, PMID:11939944, PMID:16097959).

    Mutations in the LAMA2 gene result in the loss or defective laminin-211 or merosin (α2,β2,γ1) and laminin-221 (α2,β2,γ1) heterotrimers, which are the underlying cause of disease in MDC1A. LAMA2 mutations have been identified in 25% of cases of congenital muscular dystrophy and partial laminin alpha2 chain deficiency has been linked with myopathy resembling inclusion body myositis (PMID:15351421, PMID:7550355, PMID:9039983, PMID:10679965, PMID:10611118, PMID:9674786, PMID:11584042, PMID:10852549).

    Laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dy(W-/-) mouse model (PMID:22322301).

    miRNAs also participate as decisive factors involved in the secondary pathogenic cascades of primary muscle disorders (PMID:19167326, PMID:17942673)

    Myasthenia gravis

    Myasthenia gravis (MG) is an autoimmune disease which can cause weakness in striated musculature due to anti-acetylcholine receptor antibodies or muscle specific kinase at the neuromuscular junction (PMID:23524069).

    It has been suggested that MMPs play a role in immune cell infiltration, basement membrane breakdown and autoimmune pathogenesis of MG. MMP-3, (which processes laminin), may have a specific pathogenic effect in this disease (PMID:21212676, PMID:18262287, PMID:12684035, PMID:21826262, PMID:18262287).

    MiRNAs have been implicated as fine-tuning regulators, controlling diverse biological processes at a post-transcriptional repression level and are important regulators of human autoimmune disease pathogenesis. In MG patients, miR-320a was significantly down-regulated and might play a role in modulation of inflammatory cytokines production. Besides that, miRNA microarrays showed a decrement of let-7 family in peripheral blood mononuclear cells (PBMCs) from MG patients compared to the healthy controls (PMID:19167326, PMID:23196978, PMID:22835429).

    Infectious neuropathies

    HTLV-1 – HAM/TSP

    It has been more than 30 years since the discovery of Human T-Lymphotropic Virus Type 1 (HTLV-1), the first human retrovirus identified. HTLV-1 infects 15-20 million people worldwide causing two major diseases: Adult T-cell Leukemia/Lymphoma and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis. HTLV-1 establishes several decades of latent infection, during which viral-host interaction determines disease segregation. PMID: 23651172, PMID: 19412195.

    T cells interact with the extracellular matrix via integrin receptors and these interactions affect both cellular localization and proliferation. However, the importance of these interactions in retrovirus-induced diseases, remains less clear. HTLV-I-related alterations in cell surface adhesion molecules may contribute to the abnormal proliferation of T cells in adult T cell leukemia (ATL) or to the abnormal localization of activated or infected T cells to the central nervous system of patients with tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). PMID: 7504369.

    The cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the CNS, thus biochemical processes in the CNS could potentially be reflected in the CSF. Changes in extracellular matrix (ECM) proteins can be studied through their analysis in the CSF. The relative levels of ECM proteins expressed in the CSF from the chronic myelopathy of TSP/HAM, and a sub-acute disease without inflammatory components, such as CJD were compared. PMID: 8370483, PMID: 8120634, PMID: 9760698.

    Changes in the activity of these systems were shown in a series of 21 patients with TSP/HAM and 19 patients with CJD, compared with a control group. A common finding in the CSF from these two groups is an increase in thrombospondin and perlecan, but with CSF showing a distinct pattern of overexpression of fibronectin, which was found to be increased in CJD patients. Interestingly, TSP/HAM patients presented significantly higher levels of Laminin in CSF analyses. PMID: 15115246.

    Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, it can produce specific substrate-cleavage fragments with independent biological activity. It can also regulate tissue architecture through effects on the ECM and intercellular junctions, and can activate, deactivate or modify the activity of signalling molecules, both directly and indirectly. Because cells have receptors (for example, integrins) for structural ECM components, MMPs can also affect cellular functions by regulating the ECM proteins with which the cells interact. In many cases, MMP cleavage of ECM substrates generates fragments that have different biological activities from their precursors. PMID: 11687497, PMID: 10508658, PMID: 17318226, PMID: 11535623.

    Matrix metalloproteinases (MMPs) have been reported to be involved in various inflammatory disorders. It has also been shown that MMP-2 and MMP-14 were capable of unmasking cryptic epitopes in laminin-5/laminin-332 in vitro. However the physiological relevance of these epitopes in vivo remain controversial. PMID: 19800930, PMID: 12837607.

    MMP-9 is expressed at high levels in the immediate postnatal hippocampus and their expression levels fall just as laminin levels increase. Delivering an MMP inhibitor to the hippocampus in vitro and in vivo controls neuron numbers through a laminin-dependent process. These results assign a critical role to MMP-9 and ECM in the activity-dependent regulation of neuron numbers in the developing hippocampus and may also help highlight disease conditions in the adult brain. This work is the first to report a role for MMP-9 in regulating neuronal survival through developmental processes that establish the functional brain. PMID: 22351756.

    Previous studies revealed that MMP-2 and MMP-9 might play important roles in the breakdown of the blood–brain barrier (BBB) in the central nervous system (CNS) of patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). PMID: 12044984.

    Initial studies of reverse zymography with CSF from TSP/HAM patients, showed the presence of TIMPs (endogenous MMP inhibitors). TIMP-2, TIMP-3 and TIMP-4 levels were significantly higher compared to controls in both TSP/HAM and inflammatory patients, while TIMP-1 was increased only in the inflammatory group. Levels of MMP-3 and MMP-9 from the TSP/HAM patients showed a significant upregulation in CSF. Overall, the imbalance between MMPs and their endogenous tissue inhibitors could be a pathogenic factor in the chronicity of TSP/HAM. PMID: 12697269.

    HTLV-1 up-regulated miRNAs may also contribute to the development of the clinical manifestation of this virus, HAM/TSP. Numerous host miRNAs are either up-regulated (miR-21, miR-93, miR-143-p3, miR-146a, miR-155) or downregulated (miR-132, miR-149, miR-873) in HTLV-1 infected cells through varied molecular mechanisms. Several deregulated host miRNAs are found to play roles in the oncogenic or neurodegenerative diseases associated with HTLV-1. PMID: 23251140.

    MiR-125b expression was significantly higher in HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis patients. Studies analysing miRNAs that exhibit altered expression patterns in HAM/TSP will likely enhance our understanding of how miRNAs participate in the progression of myelopathy and will open avenues for new therapeutic approaches. PMID: 22990976, PMID: 22808228, PMID: 22496815, PMID: 21640212, PMID: 20600265, PMID: 20017139, PMID: 19014483.

    Human immunodeficiency virus (HIV)

    HIV/AIDS has become one of the most devastating pandemics in recorded history and HIV-1 virus is responsible for the global AIDS pandemic. HIV-1 is transmitted by sexual contact across mucosal surfaces, by maternal-infant exposure, and by percutaneous inoculation. (PMID:23732522, PMID:23043157).

    Interactions between monocytes and ECM profoundly affect the manner in which these cells control HIV infection: HIV infection changes the capacity of infected monocytes that attach and spread on ECM. Attachment to ECM alters the extent of virus replication in infected cells. Besides that, HIV-1 infection of lymphocytes and monocytes leads to an increased adhesion of these cells to vascular endothelium and extracellular matrix molecules, and it also induces changes in monocyte metalloprotease activity (PMID:1640176, PMID:9852238, PMID:1506780).

    In the in vitro model of salivary ductal epithelial cells infected by HIV-1, the mRNA expression of several matrix molecules, such as laminin and fibronectin, basement membrane and oncoproteins were altered (PMID1:1311202).

    MicroRNAs (miRNAs) are an ubiquitous class of small regulatory RNAs that serve as post-transcriptional regulators of gene expression. Previous work has suggested that HIV-1 might subvert the function of the cellular miRNA machinery by expressing viral miRNAs or by dramatically altering the level of cellular miRNA expression. Moreover, HIV-1, rather than seeking to control miRNA function in infected cells, has instead evolved a mechanism to become largely invisible to cellular miRNA effector mechanisms (PMID:19167326, PMID:17855543, PMID:15601474, PMID:15722536, PMID:17663774, PMID:19220914, PMID:18299284, PMID:19729508, PMID:21911362, PMID:17322031, PMID:17906637, PMID:23592263, PMID:17917655).

    Hansen's disease

    Leprosy, also known as Hansen's disease, is a chronic infectious disease caused by Mycobacterium leprae, a microorganism that primarily infects Schwann cells in the peripheral nerves, leading to nerve damage and the development of disabilities (PMID:22988457, PMID:9874652).

    Laminins are expressed in Schwann cells and participate in their development, defective laminin signals contribute to the pathogenesis of diverse neuropathies, including neurofibromatosis and leprosy. In the basement membrane of Schwann cells alphaBeta-Dystroglycan binds to laminin alpha2, specially the G domain of laminin alpha2 chain, in turn binding to receptors on the M. leprae surface (PMID:15958125, PMID:15919224, PMID:15881032, PMID:12100448, PMID:10449784, PMID:9851927).

    MicroRNAs (miRNAs) are evolutionarily conserved, naturally abundant, small, regulatory non-coding RNAs that inhibit gene expression at the post-transcriptional level in a sequence-specific manner. Recent evidence also points to a critical role of miRNAs in infectious disease, including those of bacterial origin (PMID:19167326, PMID:14744438, PMID:23448104, PMID:19286800). The most differentially expressed miRNA in lepromatous lesions, hsa-mir-21, was up-regulated in M. leprae-infected monocytes and probably plays a role in the mechanism(s) that regulate host defence vs. persistence in human infectious disease (PMID:22286305). Expressional losses of miR-181 have also been associated with the progression of leprosy (PMID:21453975).



    Human tuberculosis (TB), is caused by the infection of the Mycobacterium tuberculosis complex and remains a global emergency. M. tuberculosis uses the glyoxalate bypass for intracellular survival in vivo. The glyoxalate pathway includes the enzyme malate synthase (MS) that has adapted to function as an adhesin biding to laminin and fibronectin. Antibodies in the C-terminal laminin/fibronectin-binding domain interfere with the binding of the MS to laminin and fibronectin which reduces the adherence of M. tuberculosis to lung epithelial cells. The addition of soluble alpha2-laminins significantly increases the adherence of M. tuberculosis to schwannoma cells (PMID:23629506, PIMD:23425167, PMID:21420161, PMID:16677310, PMID:11192500).

    Host-pathogen interactions involve Galectin-3, a multifunctional beta-galactoside which binds lectin and laminin present mainly in the cytoplasm of inflammatory cells and are also present on the cell surface. Galectin-3 can recognize mycolic acids, major constituents of M. tuberculosis cell envelope (PMID:16310777).

    Another laminin binding molecule, the laminin-binding protein (LBP) has a role in mycobacteria stability within the adherence mechanism (PMID:12149464, PMID:11123691).

    The underlying mechanisms of matrix destruction in tuberculosis remain poorly understood. However, taking into account the presence of lung extracellular matrix, it has been predicted that MMPs might play a central role. MMP-1, -2, -8 and -9 have shown a correlation with matrix degrading phenotype in tuberculosis (PMID:21659415, PMID:21416734).

    Different lines of evidence demonstrate that miRNAs play an important role in host-pathogen interactions. miRNAs regulate T-cell functions and are biomarker candidates of disease susceptibility and treatment efficacy in M. tuberculosis infection. Within this context, miR-21, miR-26a, miR-29a, and miR-142-3p play an important role in T cell immunity against M. tuberculosis infection and disease. Besides that, miR-29a, miR-155, miR-155*, miR-125b, miR-3179a, miR-147, miR-361-5p, miR-889, miR-576-3p, miR-223, miR-144*, miR-421, miR-146 and miR-424 may be potential biomarkers for diagnosis of tuberculosis or might play a role in this disease (PMID:19167326, PMID:23613882, PMID:23448104, PMID:23272999, PMID:22964481).


    Neurorosyphiles is a clinical manifestation of syphilis, it occurs when the Treponema pallidum disseminates to the central nervous system. This pathogen attaches to host tissues via extracellular matrix component laminin by laminin-binding adhesin Tp0751 which exhibits metalloprotease-like features capable of degrading host components. Tp0751-specific antibodies inhibited attachment of T. pallidum to laminin (PMID:20626434, PMID:7799839, PMID:16239550, PMID:12704124, PMID:21149586).


    Neuroborreliosis is a multisystemic disease that affects the nervous system after systemic infection with the spirochete Borrelia burgdorferi (PMID:7043737, PMID:10908149, PMID:9007596).

    A potential biomarker for neuroborreliosis is extracellular adhesion protein α-Dystroglycan. This protein is a central component of the dystrophin-glycoprotein complex (DGC) that links extracellular matrix with cytoskeleton, and interacts with different ligands, such as laminin (PMID:21843510, PMID:19303439, PMID:10508656, PMID:20625412, PMID:23395731).

    Other potential markers for neuroborreliosis are the MMPs. The pattern of cerebrospinal fluid gelatinase activity of MMP2 and MMP9 may be a useful marker for neuroborreliosis (PMID:9466528, PMID:9195108).

    Neurodegenerative diseases

    Alzheimer’s disease

    Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by a loss of memory which finally determines the clinical onset of dementia. AD is the most prevalent neurodegenerative disease in the growing population of elderly people. Alzheimer brains are histopathologically characterized by numerous senile plaques and neurofibrillary tangles. Both lesions are considered to be of pivotal importance to understand AD. In addition, genetic evidence points at the regulation of amyloid precursor protein (APP) metabolism as a key factor in the pathogenesis of AD.

    The function of APP is unknown but there is increasing evidence of the role of APP in cell-cell and/or cell-matrix interactions.

    Amyloid-derived neurotoxicity is widely considered as a main factor in explaining the neurodegenerative changes observed in AD. The neurotoxic effect of amyloid beta (Abeta) peptide, a proteolytic fragment of APP, is associated with its polymerization state as amyloid fibrils. Studies of amyloid-derived neurotoxicity in vivo have shown an increased vulnerability to neurotoxicity with aging, suggesting the participation of some age-dependent factors. PMID: 8713166, PMID: 1434542, PMID: 11323745, PMID: 10392577, PMID: 8463843, PMID: 7991613, PMID: 9662375.

    A characteristic of AD is the accumulation of plaques in the brain, and theses plaques mainly consist of aggregates of Abeta. All converging lines of evidence suggest that progressive accumulation of the Abeta plays a central role in the genesis of AD and it was long understood that Abeta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. The enzyme Acetylcholinesterase (AChE) induces Abeta fibrils formation, forming a stable complex which is highly neurotoxic. On the other hand, laminin inhibits the Abeta fibrils formation and also depolymerizates Abeta fibrils. PMID: 18537540, PMID: 17348688, PMID: 11323745, PMID: 11054814, PMID: 9372205, PMID: 9063584, PMID: 7610767.

    A growing amount of evidence indicates the involvement of extracellular matrix components, especially laminins, in the development of AD, although their role remains unclear. Laminin has proven to be an influential glycoprotein of the extracellular matrix which guides and promotes the differentiation and growth of neurons. PMID: 8488758, PMID: 9063584, PMID: 8871961, PMID: 7498414.

    The low levels of extracellular matrix protein expression may assist in CNS wound repair and regeneration, excessive extracellular matrix deposition could result in the development of hydrocephalus. As an effective inducer of extracellular matrix components, TGF-beta 1 may also contribute to the development of other neuropathological alterations, e.g., the formation of amyloid plaques in AD. PMID: 7604885.

    Laminin 1 inhibits Abeta-induced neuronal cell death by preventing the fibril formation and interaction of the Abeta peptide with cell membranes. The presence of laminin at a laminin/Abeta peptide molar ratio of 1:800 significantly inhibits the Abeta-induced apoptotic events, together with inhibition of amyloid fibril formation. Laminin was thus suggested to be an effective therapeutic agent for AD PMID: 10428072, PMID: 10353333, PMID: 9555007.

    Monji and collaborators suggested that the synthetic peptide derived from the laminin alpha1 chain might be an effective therapeutic agent for either preventing or slowing down the progression of amyloidogenesis in AD. PMID: 9714466.

    Immunocytochemistry, western blotting, and RT-PCR were used to identify the isoforms of laminin expressed in AD. The alpha 1 laminin was heavily over-expressed in the frontal cortex of AD brains, localized in reactive astrocytes of the grey and white matter, and located as punctate deposits in the senile plaques of the Alzheimer brain tissue. Antibodies against the C-terminal neurite outgrowth domain of the gamma 1 laminin showed expression of the gamma 1 laminin in GFAP-immunoreactive reactive astrocytes of the Alzheimer disease frontal cortex. PMID: 12111806.

    Levels of certain laminins in the cerebrospinal fluid (CSF) demonstrated significant differences in the chain levels in different dementias. Cerebrospinal fluid laminin or its derivatives may correlate with the pathogenesis of Alzheimer's disease (AD) and vascular dementia (VaD). The prevention of the proteolytic activity may be an effective therapeutic method for either preventing or slowing down the progression of AD and VaD. Furthermore, it was shown that performing ELISA for CSF laminins may prove to be useful for detecting the biological markers of AD and VaD. PMID: 12218253

    The 37 kDa/67 kDa laminin receptor (LRP/LR) represents a key player for cell adhesion, it is associated with the metastatic potential of solid tumours and is required for maintenance of cell viability by preventing apoptosis. The receptor represents an alternative target for therapy of viral infections, cancer and prion disorders and might play additional roles in further neurodegenerative diseases such as AD. Anti-LRP/LR antibodies, siRNAs directed against LRP mRNA, polysulfated glycanes such as pentosan polysulfate, heparan mimetics and LRP decoy mutants are promising tools for blocking or downregulating the receptor and may represent alternative therapeutics for the treatment of prion disorders, AD and metastatic cancer. PMID: 19200017, PMID: 21110766, PMID: 20515747.

    Integrins are integral membrane proteins that mediate adhesive interactions of cells with the extracellular matrix and with other cells. Neurons grown on laminin, an integrin ligand, exhibit increased resistance to glutamate-induced apoptosis. Neurons expressed integrin beta 1 and treatment of cultures with an antibody against integrin beta1 abolished the protective effect of laminin. Moreover, Neurons maintained on laminin exhibited a sustained activation of the Akt signaling pathway and increased levels of anti-apoptotic Bcl-2. These data suggest a mechanism for the neuroprotective effect of integrin-mediated signaling. PMID: 11238733; PMID: 7515758.

    Amyloid deposition is followed by the expression of beta 3-integrin, a specific marker molecule of activated endothelium. The beta 3-integrin expression is restricted to amyloid-positive vessels. PMID: 16821113.

    Immunocytochemistry, radioimmunoassay, immunoblotting, Northern analysis, and polymerase chain reaction (PCR) technique were applied to investigate the distribution of laminin and its neurite outgrowth domain in brains of neuropathologically verified cases of AD. Laminin was found as large punctate deposits in all plaques in the affected brains. Laminin synthesis was increased as assessed by RNA blotting and immunoblotting, and glial cells were heavily immunoreactive with antibodies for a neurite outgrowth-promoting peptide antigen of the beta 2 chain laminin. PMID: 1\404496.

    Recently, the physical properties of microvasculature and vessel association with microglial clusters in cortical tissue from AD individuals were investigated and classified as severe (ADsev), mild (ADmild), or nondemented controls (ND). The presence of extravascular laminin and fibrinogen and the vascular modifying factors, TNF-α and VEGF localized within clusters of activated microglia, is consistent with microglial-induced vascular remodeling in ADsev brain. Microglial-vascular reciprocal interactions could play a critical role in the amplification and perpetuation of inflammatory reactivity in AD brain. PMID: 20704556.

    The growing interest in miRNAs also extends to the area of neurodegeneration. Some of brain-restricted miRNAs have been associated with disorders such as Alzheimer's disease, Parkinson's disease or Huntington's disease. PMID: 21643950.

    Accumulating research indicates that noncoding RNAs (ncRNAs), (especially miRNAs) and long noncoding RNAs (lncRNAs), are increasingly associated with AD. Experiments employing genetic manipulations of the RNase III Dicer in animal models raised the possibility that miRNAs are important in the pathogenesis of neurodegenerative disorders like AD. PMID: 22008259, PMID: 21945006, PMID: 20953120, PMID: 20080199, PMID: 19881909, PMID: 19822222.

    Expression profiling of 328 microRNAs in anterior temporal cortex from five sporadic AD patients and five age-matched controls showed the expression of 13 microRNAs to be decreased in AD. Notably, miR-29a, -29b-1, and -9 decreased the expression of beta-amyloid cleavage enzyme 1 (BACE-1), which is one of two critical enzymes required for the cleavage of amyloid precursor protein and the generation of toxic Aβ species. PMID:18434550, PMID: 19828790, PMID: 21922512, PMID: 23054683, PMID: 22285895 .

    A single miRNA concurrently down-regulates hundreds of target mRNAs designated "targetome", and thereby fine-tunes gene expression involved in diverse cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. Recently, the molecular network of the whole human miRNA targetome was characterized by using bioinformatics tools for analysing molecular interactions on the comprehensive knowledgebase. It was described that the miRNA targetome regulated by an individual miRNA generally constitutes the biological network of functionally-associated molecules in human cells, closely linked to pathological events involved in cancers and neurodegenerative diseases. PMID: 23034144.

    Recent studies have revealed that some miRNAs such as miR-9, miR-29 family, and miR-34 family are differentially expressed in Alzheimer's disease, Parkinson's disease, and Huntington's disease. These miRNAs are also reported to act as tumour suppressors during human carcinogenesis. Cancer and neurodegenerative disorder may be influenced by common miRNA pathways that regulate differentiation, proliferation, and death of cells. PMID: 23056009.

    Microarray analysis and in situ hybridization showed that the expression of miR-107 is decreased in the brains of AD patients at the earliest stages of pathology in parallel with increased BACE-1 mRNA levels. MiR-107 down-regulation was observed in a new set of human AD samples. Yet another profiling study reported miR-9, miR-125b and miR-128 to be increased in the hippocampal region of AD affected brains. PMID: 18234899, PMID: 17314675, PMID: 20413881, PMID: 20936480, PMID: 20126538, PMID: 22285895.

    Amyloid precursor protein (APP) expression misregulation can cause genetic AD. Bioinformatics analysis identified twelve putative miRNA bindings sites located in or near the APP3'UTR variants T117C, A454G and A833C. Among those candidates, seven miRNAs, including miR-20a, miR-17, miR-147, miR-655, miR-323-3p, miR-644, and miR-153 can regulate APP expression in vitro and under physiological conditions in cells. PMID: 21982160, PMID: 22285895, PMID: 21785276, PMID: 21728971, PMID: 21720722.

    Endogenous miR-101 regulates expression of APP in human cells via a specific site located within its 3'-UTR. It was demonstrated that, across a series of human cell lines, highest expression of miR-101 levels was observed in model NT2 neurons. PMID: 21172309.

    Abundant neurochemical, neuropathological, and genetic evidence suggests that a critical number of pro-inflammatory and innate immune system-associated factors are involved in the underlying pathological pathways that drive the sporadic AD process. Most recently, a series of epigenetic factors including a select family of inducible, pro-inflammatory, NF-κB-regulated miRNAs have been shown to be significantly elevated in AD brains. These up-regulated miRNAs appear to be instrumental in reshaping the human brain transcriptome. Early reports have further indicated that miRNA neutralization employing anti-miRNA (antagomir) strategies may hold future promise in the clinical management of this insidious neurological disorder and expanding healthcare concern. PMID: 23217212.

    In neurodegenerative disease research, stress-triggered up-regulation of NF-κ B-induced miRNAs appear to play pathogenic roles in the down-regulation of the brains essential mRNA, and the initiation and propagation of pathological gene expression programs that are characteristic of the AD process. PMID: 23641256.

    These up-regulated, NF-kB-sensitive miRNAs, involved in the innate immune and inflammatory response and synaptic, neurotrophic, and amyloidogenic functions include miRNA-9, miRNA-125b, miRNA-146a, and miRNA-155. PMID: 23390425, PMID: 23301201.

    Genetic deficits and loss of function of the triggering receptor expressed in myeloid cells 2 (TREM2; encoded at chr6p21.1), a transmembrane spanning stimulatory receptor of the immunoglobulin/lectin-like gene superfamily, have been associated with deficiencies in phagocytosis and the innate immune system in AD. The literature suggests that an epigenetic mechanism involving an NF-кB-mediated, miRNA-34a-regulated down-regulation of TREM2 expression may shape innate immune and phagocytic responses that contribute to inflammatory neurodegeneration. PMID: 23462268.

    The analysis of extracellular fluid from neocortex associated with temporal lobe from AD patients indicated increased miRNAs. These miRNAs included miRNA-155 and miRNA-146a that are proinflammatory. PMID: 23516333.

    Agostini and collaborators in 2011 stated that transcription factor, TAp73, drove expression of miRNA-34a but not miRNA-34b or miRNA-34c. This was associated with a decreased expression of synaptic proteins synaptotagmin-1and syntaxin-1A. These controlled molecular reactions generally occurred in retinoid-stimulated differentiation of neuroblastoma cells. The synaptotagmin-1 protein expression changes also occurred in AD brain tissue. PMID: 22160687, PMID: 23516333.

    Recently, it was demonstrated that activator protein-1 (AP-1) regulates the transcription of miR-144 and the up-regulation of miR-144 at least partially induces the suppression of the ADAM10 protein in the presence of Abeta. In addition, it was found that miR-451, a miRNA processed from a single gene locus with miR-144, is also involved in the regulation of ADAM10 expression. Taken together, the data demonstrates miR-144/451 is a negative regulator of the ADAM10 protein and suggests a mechanistic role for miR-144/451 in AD pathogenesis. PMID: 23546882.

    Parkinson’s disease

    Neuronal loss is a common feature of many neurological disorders, including stroke, Parkinson's disease, Alzheimer's disease and traumatic brain injury. Human embryonic stem cell (hESC)-derived neural progenitors (NPs) may provide new ways of treatment for several diseases and injuries of the brain, as well as enhance our understanding of early human development.

    Human neural stem cells (hNSC) have the potential to provide novel cell-based therapies for neurodegenerative conditions such as multiple sclerosis and Parkinson's disease. Laminin was found to increase hNSC numbers as measured by this neurosphere formation. The effect of laminin was to augment the proliferation/survival of the hNSC, rather than promoting the undifferentiated state. Additionally, apoptosis was reduced in dissociated neurospheres by laminin in an integrin beta 1-dependent manner. PMID: 18651950; PMID: 19715727.

    Neural stem/precursor cells (NSPCs) have garnered much attention, because they can reveal clues about nervous system development and can possibly be used as therapeutic agents. Deciphering the factors that regulate human neural stem cells will greatly aid in their use as models of development and as therapeutic agents. The extracellular matrix (ECM) is a component of stem cell niches in vivo and regulates multiple functions in diverse cell types. Although little is known about its effects on NSPCs . NSPCs have the potential to ameliorate various neurological diseases and injuries, such as Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, stroke, and traumatic brain injury. PMID: 14659089, PMID: 14642274, PMID: 10529788, PMID: 16477652.

    Flow cytometry revealed that human NSPCs express laminin binding integrins on their cell surfaces. Namely, alpha 3, alpha 6, alpha 7, beta 1, and beta 4. Function-blocking antibodies to the alpha 6 subunit have confirmed a role for integrins in laminin-dependent migration of human NSPCs. These results define laminin and its integrin receptors as key regulators of human NSPCs. PMID: 16477652.

    Cell transplantation is a potential methodology for treatment of Parkinson's disease. However, the therapeutic effect is limited by poor viability of transplanted cells. To overcome this problem, attempts were made to prepare 3D matrices using collagen hydrogels that incorporate integrin-binding polypeptides derived from laminin-1. PMID: 22229651, PMID: 20415529.

    Amyloid fibril formation is associated with several pathologies, including Alzheimer's disease, Parkinson's disease, type II diabetes, and prion diseases. Recently, a relationship between basement membrane components and amyloid deposits has been reported. The basement membrane protein, laminin, may be involved in amyloid-related diseases, since laminin is present in amyloid plaques in Alzheimer's disease and binds to amyloid precursor protein. At least five laminin-derived peptides can form amyloid-like fibrils. Laminin-derived amyloidopgenic peptides have the potential to form amyloid-like fibrils in vivo, possibly when laminin-1 is degraded. PMID: 17348688.

    The need for an early and differential diagnosis of Parkinson's disease (PD) is undoubtedly one of the main quests of the century. An early biomarker would enable therapy to begin sooner and would, hopefully, slow down or even prevent progression of the disease. Three genes (PSMA2, LAMB2 and ALDH1A1) demonstrated high reproducibility. This result supports previous studies of gene expression profiling and may facilitate the development of biomarkers for early diagnosis of PD. PMID: 21069393.

    Molecular cues involved in directional neurite outgrowth and axonal differentiation of embryonic hippocampal neurons were studied on substrates coated in a striped 5 microns pattern with synthetic peptides from a neurite outgrowth (RDIAEIIKDI, P1543) and cell attachment (CDPGYIGSR, P364) domain of the beta 2- and beta 1-chains of laminin, respectively. Both peptides supported neuronal attachment, but only the beta 2-chain-derived P1543 promoted expression of a mature neuronal phenotype.

    The present results provide direct evidence that a 10 amino acid peptide (P1543) derived from a neurite outgrowth domain of the beta 2-chain of laminin, may be an axonal guidance and differentiation factor for embryonic hippocampal neurons in vitro. PMID: 8842805.

    Previous studies indicate that the KDI (Lys-Asp-Ile) tripeptide of gamma 1 laminin protects central neurons from mechanical trauma and excitotoxicity. Vaananen and collaborators studied the protective effect of the KDI tripeptide against 6-hydroxy-dopamine (6-OHDA) induced neurotoxicity in a rat experimental model of PD. The results demonstrated that a single unilateral injection of the KDI tripeptide into the substantia nigra before an injection of 6-OHDA protected the dopaminergic neurons from the neurotoxicity of 6-OHDA. In animals receiving 6-OHDA alone, only 1.4% of the tyrosine hydroxylase expressing dopaminergic neurons could be verified. If this much protection was achieved in humans, it would be sufficient to diminish or greatly alleviate the clinical symptoms of PD. These findings propose that the KDI tripeptide or its derivatives might offer a neuroprotective biological alternative for treatment of PD. PMID: 16810683.

    It has been reported that ECM molecules regulate monocyte activation by binding with a 67 kDa nonintegrin laminin receptor (LR). As microgliosis is a pivotal factor in propelling the progress of chronic neurodegeneration in the brain. Using 1-methyl-4-phenylpyridinium (MPP+) -treated C57 mice primary mesencephalic neuron-glia cultures as an in vitro PD model, it was observed that MPP+ treatment increased LR expression only in the mixed neuron-glia but not in microglia-enriched or microglia-depleted cultures. This suggested that MPP+-induced increase of LR expression was associated with neuron-microglia interaction. PMID: 16675848.

    The growing interest in microRNAs extended also into the area of neurodegeneration, some brain-restricted microRNAs are reported to be associated with disorders such as Alzheimer's disease, Parkinson's disease or Huntington's disease. PMID: 21643950.

    MicroRNAs (miRNAs) are small RNAs that control gene expression by binding to the 3´UTRs of mRNAs. Postmortem analysis of brain tissues and in vitro studies have identified several miRNAs implicated in PD. MiR-133b was shown to be downregulated in PD brains and to promote survival of dopaminergic neurons. MiR-433 was associated with PD through targeting the FGF20, which in turn regulates the expression of a-synuclein. MiR-7 targets a-synuclein and might regulate oxidative stress and cell death, while miR-184 and let-7 regulate dopaminergic neurons survival and activity. Recently, a miRNA profiling of PD brains identified early down-regulation of miR-34b/c, modulating mitochondrial function in areas with pathological affectation. PMID: 19904280, PMID: 23543376, PMID: 17761882, PMID: 18252210, PMID: 19628698, PMID: 20671708, PMID: 21558425, PMID: 22860903, PMID: 21922512, PMID: 21813326.

    MicroRNA expression profiling revealed decreased expression of miR-34b and miR-34c in brain areas with variable neuropathological affectation at clinical motor stages (4 and 5) (Braak stages 4 and 5) of the disease, including the amygdala, frontal cortex, substantia nigra and cerebellum. Furthermore, misregulation of miR-34b/c was detected in pre-motor stages (stages 1-3) of the disease, and thus in cases that did not receive any PD-related treatment during life. PMID: 21558425.

    MiRNA profiling of PD brains uncovered decreased expression of miR-34b and miR-34c, but not miR-133b, in affected brain areas such as the amygdala, frontal cortex, substantia nigra and cerebellum. Additionally, knock-down of miR-34b/34c in differentiated SH-SY5Y neuroblastoma cells resulted in cell death associated with altered mitochondrial activity and oxidative stress, which are consistently recognized biochemical abnormalities in PD. PMID: 21558425, PMID: 22008259, PMID: 21945006.

    To date, at least five genes have been linked with familial PD: two dominantly inherited (α-synuclein, LRRK2) and three recessive (Parkin, DJ-1 and PINK1). In addition, several genes are considered susceptibility loci including SNCA (α-synuclein), MAPT (tau), glucocerbrosidase, and the HLA-DR region. Recent reports demonstrated that the α-synuclein mRNA is under negative control by at least two microRNAs, miR-7 and miR-153. PMID: 20711177, PMID: 18987351, PMID: 19915575, PMID: 22245218.

    Recent genome-wide association studies indicate that a simple alteration of Leucine-rich repeat kinase 2 (LRRK2) gene expression may contribute to the etiology of sporadic PD. It was identified that miR-205 suppressed the expression of LRRK2 protein through a conserved-binding site at the 3' UTR of LRRK2 gene. Interestingly, miR-205 expression was significantly down-regulated in the brains of patients with sporadic PD. In addition, introduction of miR-205 prevented the neurite outgrowth defects in neurons expressing a PD-related LRRK2 R1441G mutant. Altogether, these findings suggest that down-regulation of miR-205 may contribute to the potential pathogenic elevation of LRRK2 protein in the brains of patients with sporadic PD. Conversely overexpression of miR-205 may provide an applicable therapeutic strategy to suppress the abnormal up-regulation of LRRK2 protein in PD. PMID: 23125283, PMID: 22664921.

    Recent findings demonstrated that blood samples can be used as a source of miRNA identification associated with PD. A set of six differentially expressed miRNAs were identified. While miR-1, miR-22* and miR-29 expression levels allowed to distinguish non-treated PD from healthy subjects, miR-16-2*, miR-26a2* and miR30a differentiated between treated and untreated patients. This study is innovative in contributing to the development of effective PD biomarkers. PMID: 21295623, PMID:21295133.

    Recent reports of miRNA modulators of both neuronal and immune processes (here termed NeurimmiRs) predict therapeutic potential for manipulating NeurimmiR levels in diseases affecting both the immune system and higher brain functions, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and anxiety-related disorders. PMID: 21813326.

    Chronic inflammatory demyelinating polyradiculoneuropathy

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune disorder of the peripheral nervous system, with existing expression of ECM proteins and has an important role of matrix metalloproteinases (MMPs) in its pathogenesis (PMID:21844897, PMID:23458271, PMID:10408531, PMID:10408538).

    MMPs are a family of zinc-dependent endoproteinases that play an important role in inflammation and tissue degradation (PMID:23567503). The up-regulation of MMP-2 and MMP-9, metalloproteinases which cleave laminin molecules, is a specific feature of CIDP and immunohistochemistry for matrix MMP-9 may be useful for the distinction of inflammatory and non-inflammatory neuropathies (PMID:14688206, PMID:23540404, PMID:10408538, PMID:21696493, PMID:18814268, PMID:14663052, PMID:12471459).