The Prion-Like Spreading of Alpha-Synuclein in Parkinson's Disease: Update on Models and Hypotheses

The pathological aggregation of the presynaptic protein alpha-synuclein (alpha-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson's disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological alpha-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo alpha-syn misfolding and/or neuronal internalization of aggregated alpha-syn facilitates conformational templating of endogenous alpha-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded alpha-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of alpha-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.

Automated summary

The pathological aggregation of presynaptic protein alpha-synuclein and its propagation through synaptically coupled neuroanatomical tracts are believed to underlie the progression of Parkinson's disease and other synucleinopathies. Understanding the mechanisms of alpha-synuclein propagation may provide insights into the etiology of PD and identify new therapeutic targets.