Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

TLDR

Parkinson’s disease is marked by α‑synuclein Lewy bodies and loss of midbrain dopamine neurons, yet the causal link between Lewy inclusion formation and neurodegeneration remains uncertain. In wild‑type mice, a single intrastriatal injection of synthetic α‑Syn fibrils triggered pathological α‑Syn spread, induced Lewy pathology and selective loss of substantia nigra dopamine neurons, reduced dopamine levels, and motor deficits, thereby linking α‑Syn transmission to Parkinson‑like neurodegeneration.

Abstract

Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.