The potential of brain organoids in addressing the heterogeneity of synucleinopathies.

Abstract

Synucleinopathies are a group of diseases characterized by neuronal and glial accumulation of α-synuclein (aSyn) linked with different clinical presentations, including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), Dementia with Lewy Bodies (DLB) and Multiple system atrophy (MSA). Interestingly, the structure of the aSyn aggregates can vary across different synucleinopathies. Currently, it is unclear how the aSyn protein can aggregate into diverse structures and affect distinct cell types and various brain regions, leading to different clinical symptoms. Recent advances in induced pluripotent stem cells (iPSCs)-based brain organoids (BOs) technology provide an unprecedented opportunity to define the etiology of synucleinopathies in human brain cells within their three-dimensional (3D) context. In this review, we will summarize current advances in investigating the mechanisms of synucleinopathies using BOs and discuss the scope of this platform to define mechanisms underlining the selective vulnerability of cell types and brain regions in synucleinopathies.