alpha-synuclein impairs autophagosome maturation through abnormal actin stabilization

Vesicular trafficking defects, particularly those in the autophagolysosomal system, have been strongly implicated in the pathogenesis of Parkinson's disease and related alpha-synucleinopathies. However, mechanisms mediating dysfunction of membrane trafficking remain incompletely understood. Using a Drosophila model of alpha-synuclein neurotoxicity with widespread and robust pathology, we find that human alpha-synuclein expression impairs autophagic flux in aging adult neurons. Genetic destabilization of the actin cytoskeleton rescues F-actin accumulation, promotes autophagosome clearance, normalizes the autophagolysosomal system, and rescues neurotoxicity in alpha-synuclein transgenic animals through an Arp2/3 dependent mechanism. Similarly, mitophagosomes accumulate in human alpha-synuclein-expressing neurons, and reversal of excessive actin stabilization promotes both clearance of these abnormal mitochondria-containing organelles and rescue of mitochondrial dysfunction. These results suggest that Arp2/3 dependent actin cytoskeleton stabilization mediates autophagic and mitophagic dysfunction and implicate failure of autophagosome maturation as a pathological mechanism in Parkinson's disease and related alpha-synucleinopathies. Author summary Vesicle trafficking is a central cell biological pathway perturbed in Parkinson's disease. Here we use a genetic approach to define an underlying mechanism by demonstrating that the key Parkinson's disease protein alpha-synuclein impairs maturation of autophagosomes and mitophagosomes through Arp2/3 dependent excess stabilization of cellular actin networks.

Automated summary

The study shows that the Parkinson's disease protein alpha-synuclein impairs autophagosome and mitophagosome maturation through Arp2/3 dependent excess stabilization of cellular actin networks. Genetic destabilization of actin cytoskeleton rescues the impairment caused by alpha-synuclein and rescues neurotoxicity in transgenic animals. These findings suggest a potential therapeutic target for treating Parkinson's disease and related disorders.