Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice

The accumulation of misfolded proteins is a fundamental pathogenic process in neuro-degenerative diseases. However, the factors that trigger aggregation of alpha-Synuclein (diseases. However, the factors that trigger aggregation of alpha-Synuclein (alpha-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson's disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic alpha-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting alpha-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological alpha-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with alpha-Syn amyloid fibrils assembled from recombinant human alpha-Syn induced identical consequences. Furthermore, we show for the first time that synthetic alpha-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell-cell transmission and propagation of misfolded alpha-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.