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

Neuron | Jan 3, 2018

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.

Pubmed ID: 29249285 RIS Download

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS086074
  • Agency: NINDS NIH HHS, Id: R01 NS092093
  • Agency: NIH HHS, Id: P40 OD018537
  • Agency: NINDS NIH HHS, Id: R01 NS083391
  • Agency: NICHD NIH HHS, Id: U54 HD090255
  • Agency: NINDS NIH HHS, Id: R01 NS098821
  • Agency: NIGMS NIH HHS, Id: R01 GM084947
  • Agency: NIA NIH HHS, Id: R01 AG044113

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