Immunocytochemical studies of NACP/α-synclein mediated neuronal degeneration

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NACP/α-synuclein, a soluble presynaptic protein, undergoes conformational changes and forms filamentous aggregates in neuronal and glial cells in brains with Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). We carried out immunohistochemical, immunofluolescence, and immuno-electron microscopic (EM) investigation to clarify NACP-filament formation, and subsequent intracellular alteration in neuronal and glial cells. Subjects : Brain tissues of patients with PD, DLB, and MSA were examined. Apanel of anti-NACP antibodies was employed. Results :(1) NACP-immunoreactive dystrophic neurites (Lewy neurites) were frequently observed in the brain stem of PD/DLB. They shared immunohistochemical features with Lewy bodies in neuronal processes. On immuno-EM, dystrophic neurites were composed of random aggregation of NACP-filaments at the center of processes.(2) Cellular co-localization of NACP and microtubule-associated tau protein were sometimes confirm … More ed in PD/DLB brains, and therefore its histological classification into four categories was proposed. On immuno-EM, NACP and tau were found to aggregate into two distinctive subsets of filaments in the same neuronal inclusions in PD/DLB.(3) NACP-filamentous cytoplasmic inclusions were identified in astrocytes in three of 11 MSA brains. These astrocytes contained 12- 15 nm diameter filaments having a fuzzy outer surface, and appeared to undergo cellular degradation.(4) NACP-filamentous intra-nuclear inclusions were found in neurons and oligodendrocytes in MSA, but not in astrocytes in MSA or neurons or glia in PD/DLB. Conclusions : (1) We consider that dystrophic neurites may interfere axonal transport, and subsequently cause neuronal dysfunction in PD/DLB brains. (2) Aggregation of NACP may collapse the neuronal microtubular system and trigger aggregation and hyper-phosphorylation of tau in PD/DLB brains. (3) Alteration in astrocytic function in the tissue repair process should be considered in addition to well-accepted oligodendroglial and neuronal pathology in MSA. Less