Seeding is Believing - Insights on pathological alpha-synuclein spread and toxicity from in vivo models

Intracellular inclusions comprised of alpha-synuclein (aSyn) characterize Parkinson’s disease (PD) and several other neurodegenerative disorders. Although an association between the extent of Lewy pathology and clinical symptoms is well established in PD, how these deposits originate and target vulnerable cell populations is unknown. Our recent work demonstrates that aSyn pathology can be experimentally initiated in animals and that misfolded aSyn can self-propagate via a mechanism reminiscent of prions and prionoids. Seeded pathology in animal models also spread to multiple connected nuclei in a predictable pattern consistent with neuroanatomical connectivity, recapitulating a phenomenon observed during human disease progression, ultimately leading to the dysfunction and degeneration of afflicted neurons. These models provide new perspectives on how this and other misfolded proteins may contribute to neurodegeneration in human disease.