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?-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton.


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

SUBMITTER: Ordonez DG 

PROVIDER: S-EPMC5755717 | BioStudies | 2018-01-01

REPOSITORIES: biostudies

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