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

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