p25α stimulates α-synuclein aggregation and is co-localized with aggregated α-synuclein in α-synucleinopathies

Abstract

Aggregation of the nerve cell protein α-synuclein is a characteristic of the common neurodegenerative α-synucleinopathies like Parkinson's disease and Lewy body dementia, and it plays a direct pathogenic role as demonstrated by early onset diseases caused by missense mutations and multiplication of the α-synuclein gene. We investigated the existence of α-synuclein proaggregatory brain proteins whose dysregulation may contribute to disease progression, and we identified the brain-specific p25α as a candidate that preferentially binds to α-synuclein in its aggregated state. Functionally, purified recombinant human p25a strongly stimulates the aggregation of α-synuclein in vitro as demonstrated by thioflavin-T fluorescence and quantitative electron microscopy. p25α is normally only expressed in oligodendrocytes in contrast to α-synuclein, which is normally only expressed in neurons. This expression pattern is changed in α-synucleinopathies. In multiple systems atrophy, degenerating oligodendrocytes displayed accumulation of p25α and dystopically expressed α-synuclein in the glial cytoplasmic inclusions. In Parkinson's disease and Lewy body dementia, p25α was detectable in the neuronal Lewy body inclusions along with α-synuclein. The localization in α-synuclein-containing inclusions was verified biochemically by immunological detection in Lewy body inclusions purified from Lewy body dementia tissue and glial cytoplasmic inclusions purified from tissue from multiple systems atrophy. We suggest that p25α plays a pro-aggregatory role in the common neurodegenerative disorders hallmarked by α-synuclein aggregates.