Animal models of synucleinopathies: prion-like propagation of alpha-synuclein in wild-type animals

Abstract

Accumulation of insoluble alpha-synuclein (aS) is a pathological hallmark of some neurodegenerative diseases including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed synucleinopathies. aS is deposited in a hyperphosphorylated and ubiquitinated form with β-sheet-rich fibrillar structure in diseased brain. A growing body of evidence suggests that spreading of aS pathology occur by prion-like propagation mechanisms. Our study revealed that intracerebral injection of insoluble aS into wild-type mice can induce prion-like propagation of phosphorylated aS pathology even at 1 month after injection, while injection into aS knockout mice failed to induce any pathologies. We also have demonstrated that intracerebral injection of insoluble aS into adult common marmoset resulted in spreading of aS pathologies and neurodegeneration. These in vivo experiments clearly indicate that insoluble aS has prion-like properties and it propagates through neural networks. The underlying mechanisms of aS propagation are poorly understood, however, aS propagation model animals would be useful in elucidating pathogenetic mechanisms and developing disease-modifying drugs for synucleinopathies.