Intra‐mitochondrial protein degradation alleviates alpha‐synuclein seeding and Abeta 42 aggregation.

Abstract

Mitochondria have long been implicated in Parkinson's disease, ever since the discovery that inhibitors of the mitochondrial complex I can lead to dopaminergic neuron death. We report here that intra-mitochondrial protein degradation alleviates (PFF)-induced alpha-synuclein seeding, highly relevant for the spreading of alpha-synuclein pathology. We find that interference with mitochondrial protein import as well as intra-mitochondrial proteases aggravates the aggregation profile and indeed, alpha-synuclein shows themselves as intra-mitochondrial protein. We further demonstrate that mitochondrial protein degradation is relevant for the aggregation of Abeta 42, suggesting that mitochondria are directly linked to disturbances in cytosolic protein homeostasis of aggregation prone proteins. Taken together, this draws a new picture of how mitochondrial dysfunction is involved in neurodegenerative diseases and provokes new therapeutical approaches.