Multiple system atrophy (MSA), Parkinson's disease (PD) and a group of seemingly unrelated forms ofparkinsonism share similar filamentous inclusions and it now is known that alpha-synuclein (AS) is the building block of fibrous glial and neuronal inclusions which define these disorders as synucleinopathies. Specifically, a number of advances from research in the past 4 years have shown that: 1) Mutations in the AS gene cause familial PD, 2) AS is the major component of Lewy bodies (LBs) in PD, the LB variant of Alzheimer's disease (AD) and dementia with LBs (DLB), 3) AS positive LBs occur in >60% of familial AD brains and >50% of Down's syndrome brains with AD, 4) Glial cytoplasmic inclusions (GCIs) in MSA are formed by AS filaments, 5) AS forms LB and GCI like filaments in vitro. Moreover, novel dystrophic processes in the hippocampus of PD and DLB brains are labeled by antibodies to beta- (BS) and gamma-synucleins (GS) suggesting that all 3 of these synucleins may be implicated in the brain degeneration of synucleinopathies. Further, since AS has been shown to be selectively nitrated in the hallmark inclusions of MSA and all other synucleinopathies, nitrative and/or oxidative mechanisms may underlie brain degeneration in synucleinopathies including MSA. Finally, MSA is unique among neurodegenerative movement disorders characterized by prominent synuclein pathology because oligodendroglia rather than neurons are most affected by the accumulation of filamentous AS inclusions in MSA. For these reasons, this new Program Project Grant (PPG) proposes complementary strategies to elucidate the role synucleins play in the onset/progression of MSA. Thus, the goal of the Neuropathology Core is to support the research pursued in this PPG by obtaining, characterizing and distributing postmortem brains from patients with MSA, and by providing data from these cases on the neuropathology phenotype of MSA to Core and Project investigators. Additionally, this Core will network with other investigators in this PPG to provide advice and technical support to facilitate studies by investigators in this PPG.
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