α-Synuclein Induces Mitochondrial Dysfunction Through Spectrin and the Actin Cytoskeleton

Abstract

Abnormal accumulation of the cytoplasmic protein α-synuclein in vulnerable neurons and glial is a pathological hallmark of Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, collectively termed “α-synucleinopathies.” Clinically, α-synucleinopathies are characterized by a chronic and progressive decline in motor, cognitive, behavioral, and autonomic functions, coupled with the formation of intracytoplasmic Lewy body inclusions. There are currently no disease-modifying treatments available for α-synucleinopathies, which together comprise the second most common cause of neurodegeneration. Missense mutations in the gene encoding for α-synuclein, SNCA, are associated with the familial form of Parkinson’s disease, whereas spontaneous aggregation of α-synuclein, the principal component of Lewy bodies, is associated with the sporadic form of the disease. Although a causative link between α-synuclein and neurodegeneration is clear, the mechanism of α-synuclein mediated neurotoxicity remains unclear. Thus, the intent of this thesis was to investigate pathogenic mechanism of α-synuclein mediated toxicity in the context of α-synucleinopathies. We used a combination of genetic, neuropathological and biochemical approaches to determine the mechanism of α-synuclein induced toxicity. Here we describe a new Drosophila model of α-synucleinopathy based on widespread overexpression of wild type form of human α-synuclein, which shows robust neurodegeneration, early-onset locomotor deficits, and α-synuclein aggregation. We further 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 postmortem brain tissue from patients with α-synucleinopathy. Importantly, we provide genetic and neuropathological evidence that a direct interaction of α-synuclein with spectrin initiates pathological alteration of the actin cytoskeleton and downstream neurotoxicity. Thus, our studies have the potential to provide significant molecular and cellular insight into a devastating group of neurodegenerative disorders and suggest possible therapeutic approaches for diseases with no current cure or disease-course altering treatment.