The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
John Q. Trojanowski - One of the best experts on this subject based on the ideXlab platform.
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expression of alpha beta and gamma synuclein in glial tumors and medulloblastomas
Acta Neuropathologica, 2003Co-Authors: Kar Ming Fung, Virginia M.-y. Lee, Lucy B Rorke, Benoit I Giasson, John Q. TrojanowskiAbstract:alpha-, beta- and gamma-synuclein are highly homologous proteins that are found predominantly in neurons. Abnormal accumulation of synucleins has been associated with diseases of the central nervous system particularly Parkinson's disease. Immunoreactivity of Alpha-Synuclein is demonstrated in brain tumors with neuronal differentiation and in schwannomas, whereas gamma-synuclein has been demonstrated in breast and ovarian carcinomas. The immunoreactivity of synucleins has not been described in glial tumors. Immunoreactivity of synucleins in glial cells in culture and in pathological conditions, however, suggests that synucleins may be expressed by glial tumors. We studied the expression of alpha-, beta-, and gamma-synuclein in 84 human brain tumors (24 ependymomas, 31 astrocytomas, 8 oligodendrogliomas, and 21 medulloblastomas) by immunohistochemistry. Our study demonstrates immunoreactivity for gamma-synuclein in high-grade glial tumors; immunoreactivity is found in all anaplastic ependymomas but in only 33% of ependymomas and 16% of myxopapillary ependymomas. Immunoreactivity for gamma-synuclein is noted in 63% of glioblastomas but not in other astrocytic tumors. Of medulloblastomas, 76% have immunoreactivity for either alpha- or beta-synuclein or both; no immunoreactivity for gamma-synuclein is seen in medulloblastomas.
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a hydrophobic stretch of 12 amino acid residues in the middle of alpha synuclein is essential for filament assembly
Journal of Biological Chemistry, 2001Co-Authors: Benoit I Giasson, John Q. Trojanowski, Ian V. J. Murray, Virginia M.-y. LeeAbstract:Neuronal and oligodendrocytic aggregates of fibrillar Alpha-Synuclein define several diseases of the nervous system. It is likely that these inclusions impair vital metabolic processes and compromise viability of affected cells. Here, we report that a 12-amino acid stretch ((71)VTGVTAVAQKTV(82)) in the middle of the hydrophobic domain of human Alpha-Synuclein is necessary and sufficient for its fibrillization based on the following observations: 1) human beta-synuclein is highly homologous to Alpha-Synuclein but lacks these 12 residues, and it does not assemble into filaments in vitro; 2) the rate of Alpha-Synuclein polymerization in vitro decreases after the introduction of a single charged amino acid within these 12 residues, and a deletion within this region abrogates assembly; 3) this stretch of 12 amino acids appears to form the core of Alpha-Synuclein filaments, because it is resistant to proteolytic digestion in Alpha-Synuclein filaments; and 4) synthetic peptides corresponding to this 12-amino acid stretch self-polymerize to form filaments, and these peptides promote fibrillization of full-length human Alpha-Synuclein in vitro. Thus, we have identified key sequence elements necessary for the assembly of human Alpha-Synuclein into filaments, and these elements may be exploited as targets for the design of drugs that inhibit Alpha-Synuclein fibrillization and might arrest disease progression.
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Synucleins are developmentally expressed, and Alpha-Synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000Co-Authors: Diane D. Murphy, John Q. Trojanowski, Susan M. Rueter, Virginia M.-y. LeeAbstract:alpha-, beta-, and gamma-Synuclein, a novel family of neuronal proteins, has become the focus of research interest because Alpha-Synuclein has been increasingly implicated in the pathogenesis of Parkinson's and Alzheimer's disease. However, the normal functions of the synucleins are still unknown. For this reason, we characterized alpha-, beta-, and gamma-synuclein expression in primary hippocampal neuronal cultures and showed that the onset of alpha- and beta-synuclein expression was delayed after synaptic development, suggesting that these synucleins may not be essential for synapse formation. In mature cultured primary neurons, alpha- and beta-synuclein colocalized almost exclusively with synaptophysin in the presynaptic terminal, whereas little gamma-synuclein was expressed at all. To assess the function of Alpha-Synuclein, we suppressed expression of this protein with antisense oligonucleotide technology. Morphometric ultrastructural analysis of the Alpha-Synuclein antisense oligonucleotide-treated cultures revealed a significant reduction in the distal pool of synaptic vesicles. These data suggest that one function of Alpha-Synuclein may be to regulate the size of distinct pools of synaptic vesicles in mature neurons.
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a panel of epitope specific antibodies detects protein domains distributed throughout human alpha synuclein in lewy bodies of parkinson s disease
Journal of Neuroscience Research, 2000Co-Authors: Benoit I Giasson, John Q. Trojanowski, Ross Jakes, Michel Goedert, John E Duda, Susan Leight, Virginia M.-y. LeeAbstract:To facilitate studies of the normal biology of Alpha-Synuclein, a member of a family of neuronal proteins of unknown function, and to elucidate the role of Alpha-Synuclein pathologies in neurodegenerative diseases, we generated and characterized a panel of anti-synuclein antibodies. Here we demonstrate that these antibodies recognize defined epitopes spanning the entire length of human Alpha-Synuclein, and that some of these antibodies also cross-react with zebra finch and rodent synucleins. Since Alpha-Synuclein has been reported to be a major component of Lewy bodies (LBs) in Parkinson's disease (PD), dementia with LBs and common variants of Alzheimer's disease, we performed immunohistochemical studies showing that these antibodies label numerous LBs in the PD substantia nigra, thereby localizing protein domains throughout human Alpha-Synuclein in LBs. Taken together, our data indicate that this panel of antibodies can be exploited to probe the normal biology of Alpha-Synuclein as well as the role of pathological forms of this protein in PD and related neurodegenerative synucleinopathies.
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the expression of α β and γ synucleins in olfactory mucosa from patients with and without neurodegenerative diseases
Experimental Neurology, 1999Co-Authors: John E Duda, Virginia M.-y. Lee, Usman Shah, Steven E Arnold, John Q. TrojanowskiAbstract:A family of homologous proteins known as alpha-, beta-, and gamma-synuclein are abundantly expressed in brain, especially in the presynaptic terminal of neurons. Although the precise function of these proteins remains unknown, Alpha-Synuclein has been implicated in synaptic plasticity associated with avian song learning as well as in the pathogenesis of Parkinson's disease (PD), dementia with LBs (DLB), some forms of Alzheimer's disease (AD), and multiple system atrophy (MSA). Since olfactory dysfunction is a common feature of these disorders and the olfactory receptor neurons (ORNs) of the olfactory epithelium (OE) regenerate throughout the lifespan, we used antibodies specific for alpha-, beta-, and gamma-synucleins to examine the olfactory mucosa of patients with PD, DLB, AD, MSA, and controls without a neurological disorder. Although antibodies to alpha- and beta-synucleins detected abnormal dystrophic neurites in the OE of patients with neurodegenerative disorders, similar pathology was also seen in the OE of controls. More significantly, we show here for the first time that alpha-, beta-, and gamma-synucleins are differentially expressed in cells of the OE and respiratory epithelium and that Alpha-Synuclein is the most abundant synuclein in the olfactory mucosa, where it is prominently expressed in ORNs. Moreover, alpha- and gamma-synucleins also were prominent in the OE basal cells, which include the progenitor cells of the ORNs in the OE. Thus, our data on synuclein expression within the OE may signify that synuclein plays a role in the regeneration and plasticity of ORNs in the adult human OE.
Patrik Brundin - One of the best experts on this subject based on the ideXlab platform.
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Alpha-Synuclein propagation: New insights from animal models
Movement Disorders, 2016Co-Authors: Benjamin Dehay, Patrik Brundin, Miquel Vila, Erwan Bézard, Jeffrey KordowerAbstract:Aggregation of Alpha-Synuclein is implicated in several neurodegenerative diseases collectively termed synucleinopathies. Emerging evidence strongly implicates cell-to-cell transmission of misfolded Alpha-Synuclein as a common pathogenetic mechanism in synucleinopathies. The impact of Alpha-Synuclein pathology on neuronal dysfunction and behavioral impairments is being explored in animal models. This review provides an update on how research in animal models supports the concept that misfolded Alpha-Synuclein spreads from cell to cell and describes how findings in animal models might relate to the disease process in humans. Finally, we discuss the current underlying molecular and cellular mechanisms and future therapeutic strategies targeting Alpha-Synuclein propagation.
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parkinson s disease and alpha synuclein is parkinson s disease a prion like disorder
Movement Disorders, 2013Co-Authors: Warren C Olanow, Patrik BrundinAbstract:Altered protein handling is thought to play a key role in the etiopathogenesis of Parkinson's disease (PD), as the disorder is characterized neuropathologically by the accumulation of intraneuronal protein aggregates (Lewy bodies and Lewy neurites). Attention has particularly focused on the Alpha-Synuclein protein, as it is the principal component of Lewy pathology. Moreover, point mutations in the Alpha-Synuclein gene cause rare familial forms of PD. Importantly, duplication/triplication of the wild type Alpha-Synuclein gene also cause a form of PD, indicating that increased levels of the normal Alpha-Synuclein protein is sufficient to cause the disease. Further, single nucleotide polymorphisms in the Alpha-Synuclein gene are associated with an increased risk of developing sporadic PD. Recent evidence now suggests the possibility that Alpha-Synuclein is a prion-like protein and that PD is a prion-like disease. Within cells, Alpha-Synuclein normally adopts an alpha-helical conformation. However, under certain circumstances, the protein can undergo a profound conformational transition to a beta-sheet-rich structure that polymerizes to form toxic oligomers and amyloid plaques. Recent autopsy studies of patients with advanced PD who received transplantation of fetal nigral mesencephalic cells more than a decade earlier demonstrated that typical Lewy pathology had developed within grafted neurons. This suggests that Alpha-Synuclein in an aberrantly folded, beta-sheet-rich form had migrated from affected to unaffected neurons. Laboratory studies confirm that Alpha-Synuclein can transfer from affected to unaffected nerve cells, where it appears that the misfolded protein can act as a template to promote misfolding of host Alpha-Synuclein. This leads to the formation of larger aggregates, neuronal dysfunction, and neurodegeneration. Indeed, recent reports demonstrate that a single intracerebral inoculation of misfolded Alpha-Synuclein can induce Lewy-like pathology in cells that can spread from affected to unaffected regions and can induce neurodegeneration with motor disturbances in both transgenic and normal mice. Further, inoculates derived from the brains of elderly Alpha-Synuclein-overexpressing transgenic mice have now been shown to accelerate the disease process when injected into the brains of young transgenic animals. Collectively, these findings support the hypothesis that Alpha-Synuclein is a prion-like protein that can adopt a self-propagating conformation that causes neurodegeneration. We propose that this mechanism plays an important role in the development of PD and provides novel targets for candidate neuroprotective therapies. (C) 2013 Movement Disorder Society (Less)
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effect of mutant alpha synuclein on dopamine homeostasis in a new human mesencephalic cell line
Journal of Biological Chemistry, 2002Co-Authors: Julie Lotharius, Sebastian Barg, Pia Wiekop, Cecilia Lundberg, Heather Raymon, Patrik BrundinAbstract:Mutations in Alpha-Synuclein have been linked to rare, autosomal dominant forms of Parkinson's disease. Despite its ubiquitous expression, mutant Alpha-Synuclein primarily leads to the loss of dopamine-producing neurons in the substantia nigra. Alpha-Synuclein is a presynaptic nerve terminal protein of unknown function, although several studies suggest it is important for synaptic plasticity and maintenance. The present study utilized a new human mesencephalic cell line, MESC2.10, to study the effect of A53T mutant Alpha-Synuclein on dopamine homeostasis. In addition to expressing markers of mature dopamine neurons, differentiated MESC2.10 cells are electrically active, produce dopamine, and express wild-type human Alpha-Synuclein. Lentivirus-induced overexpression of A53T mutant Alpha-Synuclein in differentiated MESC2.10 cells resulted in down-regulation of the vesicular dopamine transporter (VMAT2), decreased potassium-induced and increased amphetamine-induced dopamine release, enhanced cytoplasmic dopamine immunofluorescence, and increased intracellular levels of superoxide. These results suggest that mutant Alpha-Synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium. Interestingly, cells expressing A53T mutant Alpha-Synuclein were resistant to amphetamine-induced toxicity. Because extravesicular, cytoplasmic dopamine can be easily oxidized into reactive oxygen species and other toxic metabolites, mutations in Alpha-Synuclein might lead to Parkinson's disease by triggering protracted, low grade dopamine toxicity resulting in terminal degeneration and ultimately cell death.
Virginia M.-y. Lee - One of the best experts on this subject based on the ideXlab platform.
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expression of alpha beta and gamma synuclein in glial tumors and medulloblastomas
Acta Neuropathologica, 2003Co-Authors: Kar Ming Fung, Virginia M.-y. Lee, Lucy B Rorke, Benoit I Giasson, John Q. TrojanowskiAbstract:alpha-, beta- and gamma-synuclein are highly homologous proteins that are found predominantly in neurons. Abnormal accumulation of synucleins has been associated with diseases of the central nervous system particularly Parkinson's disease. Immunoreactivity of Alpha-Synuclein is demonstrated in brain tumors with neuronal differentiation and in schwannomas, whereas gamma-synuclein has been demonstrated in breast and ovarian carcinomas. The immunoreactivity of synucleins has not been described in glial tumors. Immunoreactivity of synucleins in glial cells in culture and in pathological conditions, however, suggests that synucleins may be expressed by glial tumors. We studied the expression of alpha-, beta-, and gamma-synuclein in 84 human brain tumors (24 ependymomas, 31 astrocytomas, 8 oligodendrogliomas, and 21 medulloblastomas) by immunohistochemistry. Our study demonstrates immunoreactivity for gamma-synuclein in high-grade glial tumors; immunoreactivity is found in all anaplastic ependymomas but in only 33% of ependymomas and 16% of myxopapillary ependymomas. Immunoreactivity for gamma-synuclein is noted in 63% of glioblastomas but not in other astrocytic tumors. Of medulloblastomas, 76% have immunoreactivity for either alpha- or beta-synuclein or both; no immunoreactivity for gamma-synuclein is seen in medulloblastomas.
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a hydrophobic stretch of 12 amino acid residues in the middle of alpha synuclein is essential for filament assembly
Journal of Biological Chemistry, 2001Co-Authors: Benoit I Giasson, John Q. Trojanowski, Ian V. J. Murray, Virginia M.-y. LeeAbstract:Neuronal and oligodendrocytic aggregates of fibrillar Alpha-Synuclein define several diseases of the nervous system. It is likely that these inclusions impair vital metabolic processes and compromise viability of affected cells. Here, we report that a 12-amino acid stretch ((71)VTGVTAVAQKTV(82)) in the middle of the hydrophobic domain of human Alpha-Synuclein is necessary and sufficient for its fibrillization based on the following observations: 1) human beta-synuclein is highly homologous to Alpha-Synuclein but lacks these 12 residues, and it does not assemble into filaments in vitro; 2) the rate of Alpha-Synuclein polymerization in vitro decreases after the introduction of a single charged amino acid within these 12 residues, and a deletion within this region abrogates assembly; 3) this stretch of 12 amino acids appears to form the core of Alpha-Synuclein filaments, because it is resistant to proteolytic digestion in Alpha-Synuclein filaments; and 4) synthetic peptides corresponding to this 12-amino acid stretch self-polymerize to form filaments, and these peptides promote fibrillization of full-length human Alpha-Synuclein in vitro. Thus, we have identified key sequence elements necessary for the assembly of human Alpha-Synuclein into filaments, and these elements may be exploited as targets for the design of drugs that inhibit Alpha-Synuclein fibrillization and might arrest disease progression.
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Synucleins are developmentally expressed, and Alpha-Synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000Co-Authors: Diane D. Murphy, John Q. Trojanowski, Susan M. Rueter, Virginia M.-y. LeeAbstract:alpha-, beta-, and gamma-Synuclein, a novel family of neuronal proteins, has become the focus of research interest because Alpha-Synuclein has been increasingly implicated in the pathogenesis of Parkinson's and Alzheimer's disease. However, the normal functions of the synucleins are still unknown. For this reason, we characterized alpha-, beta-, and gamma-synuclein expression in primary hippocampal neuronal cultures and showed that the onset of alpha- and beta-synuclein expression was delayed after synaptic development, suggesting that these synucleins may not be essential for synapse formation. In mature cultured primary neurons, alpha- and beta-synuclein colocalized almost exclusively with synaptophysin in the presynaptic terminal, whereas little gamma-synuclein was expressed at all. To assess the function of Alpha-Synuclein, we suppressed expression of this protein with antisense oligonucleotide technology. Morphometric ultrastructural analysis of the Alpha-Synuclein antisense oligonucleotide-treated cultures revealed a significant reduction in the distal pool of synaptic vesicles. These data suggest that one function of Alpha-Synuclein may be to regulate the size of distinct pools of synaptic vesicles in mature neurons.
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a panel of epitope specific antibodies detects protein domains distributed throughout human alpha synuclein in lewy bodies of parkinson s disease
Journal of Neuroscience Research, 2000Co-Authors: Benoit I Giasson, John Q. Trojanowski, Ross Jakes, Michel Goedert, John E Duda, Susan Leight, Virginia M.-y. LeeAbstract:To facilitate studies of the normal biology of Alpha-Synuclein, a member of a family of neuronal proteins of unknown function, and to elucidate the role of Alpha-Synuclein pathologies in neurodegenerative diseases, we generated and characterized a panel of anti-synuclein antibodies. Here we demonstrate that these antibodies recognize defined epitopes spanning the entire length of human Alpha-Synuclein, and that some of these antibodies also cross-react with zebra finch and rodent synucleins. Since Alpha-Synuclein has been reported to be a major component of Lewy bodies (LBs) in Parkinson's disease (PD), dementia with LBs and common variants of Alzheimer's disease, we performed immunohistochemical studies showing that these antibodies label numerous LBs in the PD substantia nigra, thereby localizing protein domains throughout human Alpha-Synuclein in LBs. Taken together, our data indicate that this panel of antibodies can be exploited to probe the normal biology of Alpha-Synuclein as well as the role of pathological forms of this protein in PD and related neurodegenerative synucleinopathies.
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the expression of α β and γ synucleins in olfactory mucosa from patients with and without neurodegenerative diseases
Experimental Neurology, 1999Co-Authors: John E Duda, Virginia M.-y. Lee, Usman Shah, Steven E Arnold, John Q. TrojanowskiAbstract:A family of homologous proteins known as alpha-, beta-, and gamma-synuclein are abundantly expressed in brain, especially in the presynaptic terminal of neurons. Although the precise function of these proteins remains unknown, Alpha-Synuclein has been implicated in synaptic plasticity associated with avian song learning as well as in the pathogenesis of Parkinson's disease (PD), dementia with LBs (DLB), some forms of Alzheimer's disease (AD), and multiple system atrophy (MSA). Since olfactory dysfunction is a common feature of these disorders and the olfactory receptor neurons (ORNs) of the olfactory epithelium (OE) regenerate throughout the lifespan, we used antibodies specific for alpha-, beta-, and gamma-synucleins to examine the olfactory mucosa of patients with PD, DLB, AD, MSA, and controls without a neurological disorder. Although antibodies to alpha- and beta-synucleins detected abnormal dystrophic neurites in the OE of patients with neurodegenerative disorders, similar pathology was also seen in the OE of controls. More significantly, we show here for the first time that alpha-, beta-, and gamma-synucleins are differentially expressed in cells of the OE and respiratory epithelium and that Alpha-Synuclein is the most abundant synuclein in the olfactory mucosa, where it is prominently expressed in ORNs. Moreover, alpha- and gamma-synucleins also were prominent in the OE basal cells, which include the progenitor cells of the ORNs in the OE. Thus, our data on synuclein expression within the OE may signify that synuclein plays a role in the regeneration and plasticity of ORNs in the adult human OE.
Michel Goedert - One of the best experts on this subject based on the ideXlab platform.
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the α synucleinopathies parkinson s disease dementia with lewy bodies and multiple system atrophy
Annals of the New York Academy of Sciences, 2006Co-Authors: Maria Grazia Spillantini, Michel GoedertAbstract:Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Neuropathologically, it is characterized by the degeneration of populations of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that the filamentous inclusions of Parkinson's disease are made of the protein Alpha-Synuclein and that rare, familial forms of Parkinson's disease are caused by missense mutations in the Alpha-Synuclein gene. Besides Parkinson's disease, the filamentous inclusions of two additional neurodegenerative diseases, namely, dementia with Lewy bodies and multiple system atrophy, have also been found to be made of Alpha-Synuclein. Recombinant Alpha-Synuclein has been shown to assemble into filaments with similar morphologies to those found in the human diseases and with a cross-beta fiber diffraction pattern. The new work has established the Alpha-Synucleinopathies as a major class of neurodegenerative disease.
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fiber diffraction of synthetic alpha synuclein filaments shows amyloid like cross beta conformation
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Louise C Serpell, Michel Goedert, John Berriman, R Jakes, R A CrowtherAbstract:Filamentous inclusions made of Alpha-Synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial cases of Parkinson's disease are associated with mutations A53T and A30P in Alpha-Synuclein. We report here the assembly properties and secondary structure characteristics of recombinant Alpha-Synuclein. Carboxy-terminally truncated human Alpha-Synuclein (1-87) and (1-120) showed the fastest rates of assembly, followed by human A53T Alpha-Synuclein, and rat and zebra finch Alpha-Synuclein. Wild-type human Alpha-Synuclein and the A30P mutant showed slower rates of assembly. Upon shaking, filaments formed within 48 h at 37 degrees C. The related proteins beta- and gamma-synuclein only assembled after several weeks of incubation. Synthetic human Alpha-Synuclein filaments were decorated by an antibody directed against the carboxy-terminal 10 amino acids of Alpha-Synuclein, as were filaments extracted from dementia with Lewy bodies and multiple system atrophy brains. Circular dichroism spectroscopy indicated that Alpha-Synuclein undergoes a conformational change from random coil to beta-sheet structure during assembly. X-ray diffraction and electron diffraction of the Alpha-Synuclein assemblies showed a cross-beta conformation characteristic of amyloid.
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a panel of epitope specific antibodies detects protein domains distributed throughout human alpha synuclein in lewy bodies of parkinson s disease
Journal of Neuroscience Research, 2000Co-Authors: Benoit I Giasson, John Q. Trojanowski, Ross Jakes, Michel Goedert, John E Duda, Susan Leight, Virginia M.-y. LeeAbstract:To facilitate studies of the normal biology of Alpha-Synuclein, a member of a family of neuronal proteins of unknown function, and to elucidate the role of Alpha-Synuclein pathologies in neurodegenerative diseases, we generated and characterized a panel of anti-synuclein antibodies. Here we demonstrate that these antibodies recognize defined epitopes spanning the entire length of human Alpha-Synuclein, and that some of these antibodies also cross-react with zebra finch and rodent synucleins. Since Alpha-Synuclein has been reported to be a major component of Lewy bodies (LBs) in Parkinson's disease (PD), dementia with LBs and common variants of Alzheimer's disease, we performed immunohistochemical studies showing that these antibodies label numerous LBs in the PD substantia nigra, thereby localizing protein domains throughout human Alpha-Synuclein in LBs. Taken together, our data indicate that this panel of antibodies can be exploited to probe the normal biology of Alpha-Synuclein as well as the role of pathological forms of this protein in PD and related neurodegenerative synucleinopathies.
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Binding of Alpha-Synuclein to brain vesicles is abolished by familial Parkinson's disease mutation.
The Journal of biological chemistry, 1998Co-Authors: Poul Jensen, Ross Jakes, Morten Nielsen, Carlos G. Dotti, Michel GoedertAbstract:The presynaptic protein Alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease. First, two missense mutations A30P and A53T cause inheritable early onset Parkinson's disease in some families. Secondly, Alpha-Synuclein is present in Lewy bodies of affected nerve cells in the predominant sporadic type of Parkinson's disease as well as in dementia with Lewy bodies. We demonstrate in the rat optic system that a portion of Alpha-Synuclein is carried by the vesicle-moving fast component of axonal transport and that it binds to rat brain vesicles through its amino-terminal repeat region. We find Alpha-Synuclein with the A30P mutation of familial Parkinson's disease devoid of vesicle-binding activity and propose that mutant Alpha-Synuclein may accumulate, leading to assembly into Lewy body filaments.
Eliezer Masliah - One of the best experts on this subject based on the ideXlab platform.
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in vivo imaging of α synuclein in mouse cortex demonstrates stable expression and differential subcellular compartment mobility
PLOS ONE, 2010Co-Authors: Vivek K Unni, Tamily A Weissman, Eliezer Masliah, Edward Rockenstein, Pamela J Mclean, Bradley T HymanAbstract:BACKGROUND Regulation of Alpha-Synuclein levels within cells is thought to play a critical role in Parkinson's Disease (PD) pathogenesis and in other related synucleinopathies. These processes have been studied primarily in reduced preparations, including cell culture. We now develop methods to measure Alpha-Synuclein levels in the living mammalian brain to study in vivo protein mobility, turnover and degradation with subcellular specificity. METHODOLOGY/PRINCIPAL FINDINGS We have developed a system using enhanced Green Fluorescent Protein (GFP)-tagged human Alpha-Synuclein (Syn-GFP) transgenic mice and in vivo multiphoton imaging to measure Alpha-Synuclein levels with subcellular resolution. This new experimental paradigm allows individual Syn-GFP-expressing neurons and presynaptic terminals to be imaged in the living mouse brain over a period of months. We find that Syn-GFP is stably expressed by neurons and presynaptic terminals over this time frame and further find that different presynaptic terminals can express widely differing levels of Syn-GFP. Using the fluorescence recovery after photobleaching (FRAP) technique in vivo we provide evidence that at least two pools of Syn-GFP exist in terminals with lower levels of mobility than measured previously. These results demonstrate that multiphoton imaging in Syn-GFP mice is an excellent new strategy for exploring the biology of Alpha-Synuclein and related mechanisms of neurodegeneration. CONCLUSIONS/SIGNIFICANCE In vivo multiphoton imaging in Syn-GFP transgenic mice demonstrates stable Alpha-Synuclein expression and differential subcellular compartment mobility within cortical neurons. This opens new avenues for studying Alpha-Synuclein biology in the living brain and testing new therapeutics for PD and related disorders.
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selective molecular alterations in the autophagy pathway in patients with lewy body disease and in models of α synucleinopathy
PLOS ONE, 2010Co-Authors: Leslie Crews, Edward Rockenstein, Douglas Galasko, Brian Spencer, Paula Desplats, Christina Patrick, Amy Paulino, Lawrence A Hansen, Anthony Adame, Eliezer MasliahAbstract:BACKGROUND Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by Alpha-Synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in Alpha-Synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in Alpha-Synuclein transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying Alpha-Synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural analysis revealed the presence of abundant and abnormal autophagosomes. Similar alterations were observed in the brains of Alpha-Synuclein transgenic mice. Intra-cerebral infusion of rapamycin, an inhibitor of mTor, or injection of a lentiviral vector expressing Atg7 resulted in reduced accumulation of Alpha-Synuclein in transgenic mice and amelioration of associated neurodegenerative alterations. CONCLUSIONS/SIGNIFICANCE This study supports the notion that defects in the autophagy pathway and more specifically in mTor and Atg7 are associated with neurodegeneration in DLB cases and Alpha-Synuclein transgenic models and supports the possibility that modulators of the autophagy pathway might have potential therapeutic effects.
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β amyloid peptides enhance α synuclein accumulation and neuronal deficits in a transgenic mouse model linking alzheimer s disease and parkinson s disease
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Eliezer Masliah, Edward Rockenstein, Isaac Veinbergs, Yutaka Sagara, Margaret Mallory, Makoto Hashimoto, Lennart MuckeAbstract:Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of beta-amyloid and Alpha-Synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human beta-amyloid peptides, Alpha-Synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before Alpha-Synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more Alpha-Synuclein-immunoreactive neuronal inclusions than Alpha-Synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in Alpha-Synuclein singly tg mice. beta-Amyloid peptides promoted aggregation of Alpha-Synuclein in a cell-free system and intraneuronal accumulation of Alpha-Synuclein in cell culture. beta-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of Alpha-Synuclein and exacerbating Alpha-Synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of beta-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.
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dopaminergic loss and inclusion body formation in α synuclein mice implications for neurodegenerative disorders
Science, 2000Co-Authors: Eliezer Masliah, Edward Rockenstein, Isaac Veinbergs, Yutaka Sagara, Margaret Mallory, Makoto Hashimoto, Ayako Takeda, Abbyann Sisk, Lennart MuckeAbstract:To elucidate the role of the synaptic protein Alpha-Synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human Alpha-Synuclein were generated. Neuronal expression of human Alpha-Synuclein resulted in progressive accumulation of Alpha-Synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type Alpha-Synuclein may play a causal role in Parkinson's disease and related conditions.
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abnormal distribution of the non abeta component of alzheimer s disease amyloid precursor alpha synuclein in lewy body disease as revealed by proteinase k and formic acid pretreatment
Laboratory Investigation, 1998Co-Authors: Atsushi Takeda, Margaret Mallory, Makoto Hashimoto, M Sundsumo, L A Hansen, Abbyanne Sisk, Eliezer MasliahAbstract:The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP) (also known as Alpha-Synuclein) is a presynaptic terminal molecule that abnormally accumulates in the plaques of Alzheimer's disease (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffuse Lewy body disease, and Parkinson's disease. To better understand the distribution of NACP/Alpha-Synuclein and its fragments in the LB-bearing neurons and neurites, as well as to clarify the patterns of NACP/Alpha-Synuclein compartmentalization, we studied NACP/Alpha-Synuclein immunoreactivity using antibodies against the C-terminal, N-terminal, and NAC regions after Proteinase K and formic acid treatment in the cortex of patients with LBs. Furthermore, studies of the subcellular localization of NACP/Alpha-Synuclein within LB-bearing neurons were performed by immunogold electron microscopy. These studies showed that the N-terminal antibody immunolabeled the LBs and dystrophic neurites with great intensity and, to a lesser extent, the synapses. In contrast, the C-terminal antibody strongly labeled the synapses and, to a lesser extent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/Alpha-Synuclein immunoreactivity with the C-terminal antibody, it diminished the N-terminal NACP/Alpha-Synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas without pretreatment only slight anti-NAC immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAC immunostaining of LBs, plaques, and glial cells. Ultrastructural analysis revealed that NACP/Alpha-Synuclein immunoreactivity was diffusely distributed within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/Alpha-Synuclein might play an important role in the pathogenesis of disorders associated with LBs.
