The approach for disease modification based on pathogenesis of synucleinopathy

Abstract

Lewy bodies, Lewy neurites, and glial cytoplasmic inclusion in the brain constitute the main histopathological features of α–synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. They comprise amyloid–like fibrils composed of α–synuclein (αS), a small protein (～14kDa). Because the aggregation of αS in the brain has been implicated as a critical step in the development of α–synucleinopathies, the researches for biomarkers and disease–modifying therapies (DMT) have focused on the pathogenesis of αS and its aggregation process in the brain. We previously found that αS and amyloid β–protein (Aβ) acted as seeds and affected each other's aggregation pathways in vitro. In addition, we recently reported that cerebrospinal fluid (CSF) levels of αS are correlated with some clinical symptoms and CSF levels of other pathogenic proteins such as Aβ1–42, tau, and phosphorylated tau in drug–naïve PD patients.

Although αS aggregates from a monomer to assemblies such as oligomers, protofibrils and mature fibrils, the early intermediate aggregates, that is, oligomers have been considered to be most toxic species in the pathogenesis of α–synucleinopathies. We previously reported that phenolic metabolites by gut microbiota inhibited αS oligomerization and were effective in modulating the development and progression of motor dysfunction in a Drosophila model of α–synucleinopathy. The elucidation of αS pathogenesis is expected to develop biomarkers and DMT for α–synucleinopathies.