Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007758 (cerebellar ataxia)
 3,609 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous studies of the past years have established the clinical features, course and neuropathology characterizing multiple system atrophy (MSA). Clinically, two motor subtypes can be classified based on the predominance of a parkinsonian syndrome refractory to L-dopa and cerebellar ataxia. 80% of the cases involve MSA-P (the parkinsonian variant of MSA) and 20% MSA-C (cerebellar variant of MSA). Virtually all of these patients show disturbances of autonomic and urogenital function, half of the patients also exhibit pyramidal signs. Neuropathologically, MSA-C is based on an olivopontocerebellar atrophy (OPCA) and MSA-P on striatonigral degeneration (SND). However, a combination of OPCA and SND pathologies is observed in most cases. Recent evidence suggests that a key pathogenetic role may be played by glial alpha synuclein-containing inclusion bodies, which might lead to neuronal dysfunction and ultimately to cell loss. There is no therapy known to be effective in treating the motor disorders of MSA-C. By contrast, L-dopa replacement is at least transiently effective in about 30% of patients with MSA-P. Currently, initial efforts are being undertaken throughout Europe to develop neuroprotective solutions. Experiments are underway to test whether neurotransplantation by striatal grafting is a suitable method for inducing a clinically relevant response to L-dopa. Neurologically, the options for treating orthostatic hypertension and urogenital disorders are often overlooked.
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PMID:[Diagnosis and therapy of multiple system atrophy]. 1144 23

Multiple system atrophy (MSA) is a rare and extremely debilitating progressive neurodegenerative disease characterized by variable combinations of parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal dysfunction. MSA is a unique synucleinopathy, in which alpha synuclein-rich aggregates are present in the cytoplasm of oligodendroglia. The precise origin of the alpha synuclein (aSyn) found in the glial cytoplasmic inclusions (GCIs) as well the mechanisms of neurodegeneration in MSA remain unclear. Despite this fact, cell and animal models of MSA rely on oligodendroglial overexpression of aSyn. In the present study, we utilized a novel oligotrophic AAV, Olig001, to overexpress aSyn specifically in striatal oligodendrocytes of rats and nonhuman primates in an effort to further characterize our novel viral vector-mediated MSA animal models. Using two cohorts of animals with 10-fold differences in Olig001 vector titers, we show a dose-dependent formation of MSA-like pathology in rats. High titer of Olig001-aSyn in these animals were required to produce the formation of pS129+ and proteinase K resistant aSyn-rich GCIs, demyelination, and neurodegeneration. Using this knowledge, we injected high titer Olig001 in the putamen of cynomolgus macaques. After six months, histological analysis showed that oligodendroglial overexpression of aSyn resulted in the formation of hallmark GCIs throughout the putamen, demyelination, a 44% reduction of striatal neurons and a 12% loss of nigral neurons. Furthermore, a robust inflammatory response similar to MSA was produced in Olig001-aSyn NHPs, including microglial activation, astrogliosis, and a robust infiltration of T cells into the CNS. Taken together, oligodendroglial-specific viral vector-mediated overexpression of aSyn in rats and nonhuman primates faithfully reproduces many of the pathological disease hallmarks found in MSA. Future studies utilizing these large animal models of MSA would prove extremely valuable as a pre-clinical platform to test novel therapeutics that are so desperately needed for MSA.
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PMID:Viral-based rodent and nonhuman primate models of multiple system atrophy: Fidelity to the human disease. 3322 32