Molecular pathomechanisms in alpha-synucleinopathis

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In 2002, we carried out immunohistochemical examinations of the cerebella of patients with Parkinson's disease (PD), diffuse Lewy body disease (DLBD) or multiple system atrophy (MSA), using antibodies specific for alpha-synuclein (aS). aS-positive doughnut-shaped structures were found occasionally in the cerebellar molecular layer in some of these patients. Double-labeling immunofluorescence and immunoelectron microscopy studies revealed that these aS-positive doughnut-shaped structures were located in the GFAP-positive radial processes of Bergmann glia, corresponding to the outer area of Lewy body (LB)-like inclusions, and consisted of granulo-filamentous structures. These findings indicate that, although not frequently, Bergmann glia of the cerebellum are also the targets of aS pathology in alpha-synucleinopathies.In 2003, we immunohistochemically examined the MSA brain, using specific antibodies against aS and beta-synuclein(bS). aS-positive filamentous aggregates were frequently fo … More und in neurons in the pontine and inferior olivary nuclei. No abnormal accumulation of aS was noted in Purkinje cells. In contrast, bS accumulation occurred extensively in Purkinje cells, and only minimally in pontine and olivary neurons. Thus, neuronal aS inclusions appear to occur only rarely in neurons in which bS accumulates. These findings support the possibility that bS is a negative regulator of aS aggregation.In 2004, we performed immunohistochemical staining of brain tissue from patients with various neurodegenerative disorders, using an affinity-purified polyclonal antibody raised against NEDD8 that did not cross-react with ubiquitin. In LB disease, NEDD8 immunoreactivity was present in almost all of the LBs and Lewy neurites. Moreover, NEDD8 immunoreactivity was found in a variety of ubiquitinated inclusions, including neuronal and oligodendroglial inclusions in multiple system atrophy, neurofibrillary tangles in Alzheimer's disease, ubiquitinated inclusions in motor neurone disease, and intranuclear inclusions in triplet repeat diseases. These findings suggest that NEDD8 is involved in the formation of various ubiquitinated inclusions via the ubiquitin-proteasome system. Less