α-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton

Genetics and neuropathology strongly link alpha-synuclein aggregation and neurotoxicity to the pathogenesis of Parkinson's disease and related alpha-synucleinopathies. Here we describe a new Drosophila model of alpha-synucleinopathy based on widespread expression of wild-type human alpha-synuclein, which shows robust neurodegeneration, early-onset locomotor deficits, and abundant alpha-synuclein aggregation. We use results of forward genetic screening and genetic analysis in our new model to demonstrate that alpha-synuclein expression promotes reorganization of the actin filament network and consequent mitochondrial dysfunction through altered Drp1 localization. Similar changes are present in a mouse alpha-synucleinopathy model and in postmortem brain tissue from patients with alpha-synucleinopathy. Importantly, we provide evidence that the interaction of alpha-synuclein with spectrin initiates pathological alteration of the actin cytoskeleton and downstream neurotoxicity. These findings suggest new therapeutic approaches for alpha-synuclein induced neurodegeneration.