myelin-basic-protein and Parkinson-Disease

Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Autoantigens; Autoimmunity; Glatiramer Acetate; Humans; Immunization, Passive; Immunologic Factors; Immunomodulation; Myelin Basic Protein; Nerve Regeneration; Neurodegenerative Diseases; Neuroprotection; Parkinson Disease; Peptide Fragments; Peptides; Proteostasis Deficiencies; Spinal Cord Injuries; Stroke

Parkinson's disease (PD) and multiple system atrophy (MSA) have overlapping symptoms, challenging an early diagnosis. Diagnostic accuracy is important because PD and MSA have a different prognosis and response to treatment. Here, we aimed to evaluate the diagnostic value of brain-specific structural proteins in cerebrospinal fluid (CSF) of PD and MSA patients, as well as their association with cognitive decline.. CSF samples were collected from patients with clear signs of parkinsonism, but with uncertain diagnosis at the time of inclusion. Clinical diagnoses of PD (n = 55) and MSA (n = 22) were established after 3 and 10 years of follow-up and re-evaluated after 12 years, according to the most updated clinical criteria. CSF from controls (n = 118) was studied for comparison. Neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B) and myelin basic protein (MBP) levels in CSF were measured using ELISA. Protein levels were also correlated with cognitive decline, i.e. worsening of the mini mental state examination (MMSE) over a period of three years.. MBP concentrations were increased in MSA compared to PD and controls (p < 0.005) and could differentiate MSA and PD with high accuracy (AUC = 0.781; p < 0.001). Concentrations of MPB, GFAP and S100B, but not NSE, were significantly elevated in PD patients compared to controls (p = 0.05). None of the brain-specific structural proteins correlated with MMSE progression.. Our results demonstrate that MBP differentiates PD from MSA at early stages of the disease, indicating that demyelination and axonal damage may already occur in early stages of MSA.

Topics: Aged; Biomarkers; Cohort Studies; Diagnosis, Differential; Female; Glial Fibrillary Acidic Protein; Humans; Male; Middle Aged; Multiple System Atrophy; Myelin Basic Protein; Parkinson Disease; S100 Calcium Binding Protein beta Subunit

The synucleinopathy underlying multiple system atrophy (MSA) is characterized by the presence of abundant amyloid inclusions containing fibrillar α-synuclein (α-syn) aggregates in the brains of the patients and is associated with an extensive neurodegeneration. In contrast to Parkinson's disease (PD) where the pathological α-syn aggregates are almost exclusively neuronal, the α-syn inclusions in MSA are principally observed in oligodendrocytes (OLs) where they form glial cytoplasmic inclusions (GCIs). This is intriguing because differentiated OLs express low levels of α-syn, yet pathogenic amyloid α-syn seeds require significant amounts of α-syn monomers to feed their fibrillar growth and to eventually cause the buildup of cytopathological inclusions. One of the transgenic mouse models of this disease is based on the targeted overexpression of human α-syn in OLs using the PLP promoter. In these mice, the histopathological images showing a rapid emergence of S129-phosphorylated α-syn inside OLs are considered as equivalent to GCIs. Instead, we report here that they correspond to the accumulation of phosphorylated α-syn monomers/oligomers and not to the appearance of the distinctive fibrillar α-syn aggregates that are present in the brains of MSA or PD patients. In spite of a propensity to co-sediment with myelin sheath contaminants, the phosphorylated forms found in the brains of the transgenic animals are soluble (>80%). In clear contrast, the phosphorylated species present in the brains of MSA and PD patients are insoluble fibrils (>95%). Using primary cultures of OLs from PLP-αSyn mice we observed a variable association of S129-phosphorylated α-syn with the cytoplasmic compartment, the nucleus and with membrane domains suggesting that OLs functionally accommodate the phospho-α-syn deriving from experimental overexpression. Yet and while not taking place spontaneously, fibrillization can be seeded in these primary cultures by challenging the OLs with α-syn preformed fibrils (PFFs). This indicates that a targeted overexpression of α-syn does not model GCIs in mice but that it can provide a basis for seeding aggregation using PFFs. This approach could help establishing a link between α-syn aggregation and the development of a clinical phenotype in these transgenic animals.

Topics: alpha-Synuclein; Amyloid; Animals; Brain; Cells, Cultured; Humans; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal; Multiple System Atrophy; Myelin Basic Protein; Myelin Proteolipid Protein; Neurons; Oligodendroglia; Parkinson Disease; Phosphorylation; Phosphoserine; Promoter Regions, Genetic; Protein Aggregates; Protein Multimerization

Topics: Aged; Aged, 80 and over; Aging; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; Cells, Cultured; Disease Models, Animal; Female; Humans; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Myelin Basic Protein; Myelin Sheath; Neurons; Parkinson Disease; Phospholipids; Presenilin-1

Naturally occurring autoantibodies (NAbs) against a number of potentially disease-associated cellular proteins, including Amyloid-beta1-42 (Abeta1-42), Alpha-synuclein (Asyn), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and S100 calcium binding protein B (S100B) have been suggested to be associated with neurodegenerative disorders, in particular Alzheimer's (AD) and Parkinson's disease (PD). Whereas the (reduced) occurrence of specific NAbs in AD is widely accepted, previous literature examining the relation of these NAb titres between PD patients and controls, as well as comparing these levels with demographic and clinical parameters in PD patients have produced inconsistent findings. We therefore aimed, in a cross-sectional approach, to determine serum titres of the above NAbs in a cohort of 93 PD patients (31 of them demented) and 194 controls. Levels were correlated with demographic and clinical variables, cerebrospinal fluid Abeta1-42, total tau and phospho-tau levels, as well as with single nucleotide polymorphisms (SNPs) of genes which either have been reported to influence the immune system, the amyloid cascade or the occurrence of PD (ApoE, GSK3B, HLA-DRA, HSPA5, SNCA, and STK39). The investigated NAb titres were neither significantly associated with the occurrence of PD, nor with demographic and clinical parameters, neurodegenerative markers or genetic variables. These results argue against a major potential of blood-borne parameters of the adaptive immune system to serve as trait or state markers in PD.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Apolipoproteins E; Autoantibodies; Case-Control Studies; Cross-Sectional Studies; Endoplasmic Reticulum Chaperone BiP; Enzyme-Linked Immunosorbent Assay; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heat-Shock Proteins; HLA-DR alpha-Chains; Humans; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Parkinson Disease; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; S100 Calcium Binding Protein beta Subunit; Statistics, Nonparametric

To check whether glial cells have the ability to elicit adaptive immune response in Parkinson's disease and whether a change in this immune response can be observed over time. There is an increasing evidence that glial cells are involved in the neurodegenerative process in PD, in addition to neuronal structures. Measurement of autoantibodies against proteins of oligodendrocytes may serve as an indirect method to assess the level of glial cells activation or degeneration under in vivo conditions. Serum samples from 26 PD patients were collected twice, at baseline and after mean of 13 months. In addition, serum samples from 13 healthy controls matched for age and gender were assessed at one time point. IgG and IgM autoantibodies against myelin-oligodendrocyticglycoprotein (MOG), myelin basic protein (MBP), myelin-associated glycoprotein (MAG) and proteolipoprotein (PLP) were measured in all investigated subjects by a commercially available ELISA system (Mediagnost, Germany). In a group of PD significant decrease of IgG titers was observed for anti-MAG autoantibodies over the investigated time period (p<0.05). For IgM antibodies, we observed statistically significant decrease in anti-MAG autoantibodies in the follow-up period (p<0.05) and increase in anti-MBP and anti-PLP autoantibodies (p<0.05). All antibody titers differed significantly between healthy control subjects and PD patients. Our study provides the evidence for the presence of humoral response against some glial derived antigens in PD. The increasing levels of anti MBP IgG and IgM might point to the value of this marker for monitoring disease progression.

Topics: Autoantibodies; Female; Humans; Immunity, Humoral; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neuroglia; Parkinson Disease

Mutations in the LRRK2 (Leucine-Rich Repeat Kinase 2) gene are the most common cause of autosomal dominant Parkinson's disease. LRRK2 has multiple functional domains including a kinase domain. The kinase activity of LRRK2 is implicated in the pathogenesis of Parkinson's disease. Developing an assay to understand the mechanisms of LRRK2 kinase activity is important for the development of pharmacologic and therapeutic applications. Here, we describe how to measure in vitro LRRK2 kinase activity and its inhibition.

Topics: Cell Line, Transformed; Enzyme Activation; Enzyme Assays; Gene Expression Regulation; HEK293 Cells; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Myelin Basic Protein; Parkinson Disease; Phosphorylation; Protein Serine-Threonine Kinases; Recombinant Fusion Proteins

Although significant effects of interferon-gamma (IFN-gamma) on glial cells are well documented, information on the expression level and localization of glial IFN-gamma receptors (IFN-gamma-R) in the human central nervous system (CNS) is sparse. To examine the glial expression of IFN-gamma-R in the human CNS, immunohistochemistry and quantitative analyses were performed on Alzheimer disease hippocampus, Parkinson disease substantia nigra, amyotrophic lateral sclerosis spinal cord and corresponding areas from non-neurological cases. Almost all IFN-gamma-R-positive (IFN-gamma-R(+)) cells corresponded to GFAP-positive (GFAP(+)) astrocytes, while none of IFN-gamma-R(+) cells corresponded to IBA1-positive (IBA1(+)) microglia or MBP-positive (MBP(+)) oligodendrocytes in these neurological cases. We observed a similar pattern of glial IFN-gamma-R expression in non-neurological cases. Also, we quantitatively analyzed the IFN-gamma-R expression by cultured human glial cells using immunocytochemistry and reverse transcription polymerase chain reaction (RT-PCR). In contrast to in vivo results, almost all IFN-gamma-R(+) cells were IBA1(+) in microglial cultures, GFAP(+) in astrocytic cultures and MBP(+) in oligodendrocytic cultures. Moreover, no significant difference in IFN-gamma-R mRNA expression was found for these glial cell types by RT-PCR. These results suggest that the microglial and oligodendrocytic expression levels of IFN-gamma-R are much lower than the astrocytic expression levels in the human CNS in vivo, whereas all three types of glial cells constitutively express IFN-gamma-R when cultured in vitro.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Brain; Calcium-Binding Proteins; Cells, Cultured; DNA-Binding Proteins; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Interferon gamma Receptor; Male; Microfilament Proteins; Middle Aged; Myelin Basic Protein; Neuroglia; Parkinson Disease; Receptors, Interferon; Spinal Cord

In a search for novel target genes related to Parkinson's disease (PD), two full-length cDNA libraries were constructed from a human normal substantia nigra (SN) and a PD patient's SN. An analysis of the gene expression profiles between them was done using the expressed sequence tags (ESTs) frequency. Data for the differently expressed genes were verified by quantitative real-time RT-PCR, immunohistochemical analysis and a cell death assay. Among the 76 genes identified with a significant difference (P > 0.9), 21 upregulated genes and 13 downregulated genes were confirmed to be differentially expressed in human PD tissues and/or in an MPTP-treated mice model by quantitative real-time RT-PCR. Among those genes, an immunohistochemical analysis using an MPTP mice model for alpha-tubulin including TUBA3 and TUBA6 showed that the protein levels are downregulated, as well as the RNA levels. In addition, MBP, PBP and GNAS were confirmed to accelerate cell death activity, whereas SPP1 and TUBA3 to retard this process. Using an analysis of ESTs frequency, it was possible to identify a large number of genes related to human PD. These new genes, MBP, PBP, GNAS, SPP1 and TUBA3 in particular, represent potential biomarkers for PD and could serve as useful targets for elucidating the molecular mechanisms associated with PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Biomarkers; Cell Death; Chromogranins; Cytoskeletal Proteins; Expressed Sequence Tags; Gene Library; Genetic Predisposition to Disease; Genetic Techniques; GTP-Binding Protein alpha Subunits, Gs; Guanine Nucleotide Exchange Factors; Humans; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myelin Basic Protein; Nerve Tissue Proteins; Neurotoxins; Osteopontin; Parkinson Disease; Reverse Transcriptase Polymerase Chain Reaction; Substantia Nigra; Transcription Factors

Myelin basic protein (MBP) consists of several components or charge isomers (C-1 through C-8) generated by one or a combination of posttranslational modifications. One of these, C-8, has been shown to contain citrulline (Cit) at defined sites formed by deimination of six arginyl residues. This unusual modification has allowed us to raise antibodies specific for this charge isomer only. To do this, a synthetic peptide, Gly-Cit-Cit-Cit-Cit, was coupled to keyhole limpet hemocyanin and injected into rabbits. The antibodies so generated reacted only with C-8 and not with any of the other charge isomers. A second antibody fraction was raised against the synthetic peptide ACitHGFLPCitHR naturally occurring between residues 24 and 33 of C-8 (all other charge isomers contain R instead of Cit at positions 25 and 31). These antibodies preferred C-8 but reacted with the other charge isomers, to the extent of approximately 25-30% of the reactivity shown with C-8. In studies with C-8 from multiple sclerosis (MS) MBP, much greater reactivity was obtained with these antibodies when compared with their reactivity with C-8 from normal MBP. Because the total number of Cit residues in C-8 from MS and normal MBP is the same, the difference in reactivity may be related to structural factors. The antibodies raised with the tetra-Cit peptide were reacted with three pairs of synthetic peptides: 24ARHGFLPRHR33 and ACitHGFLPCitHR; 120GQRPGFGYGGRAS132 and GQCitPGFGYGGCitAS; and 157GGRDSRSGSPMARR170 and GGCitDSRSGSPMACitR. They reacted only with the Cit-containing peptides in the order 157-170 greater than 120-130 greater than 24-33.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alzheimer Disease; Antibodies; Brain; Electrochemistry; Enzyme-Linked Immunosorbent Assay; Humans; Huntington Disease; Isomerism; Multiple Sclerosis; Myelin Basic Protein; Parkinson Disease; Peptides; Reference Values

Topics: Autoantibodies; Behcet Syndrome; Diagnosis, Differential; Humans; Multiple Sclerosis; Myelin Basic Protein; Parkinson Disease; Radioimmunoassay