Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 108-124.e6 |
| Journal | Neuron |
| Volume | 97 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 3 2018 |
Bibliographical note
Funding Information:Fly stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537), the Vienna Drosophila Resource Center, H. Bellen, S. Bogdan, R. Dubreuil, C. Potter, T. Schwarz, and D. Williams were used in this study. We thank the Transgenic RNAi Project (TRiP) at Harvard Medical School (NIH-NIGMS R01GM084947) for making transgenic RNAi stocks. Monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biology, Iowa City, IA 52242. We thank Ms. Joyce Meints for technical assistance with mouse brain tissue processing. We acknowledge the Harvard Neurodiscovery Center Enhanced Neuroimaging Facility staff for assistance with confocal imaging and 3D reconstruction and the Harvard Center for Biological Imaging staff for insightful comments on super-resolution sample preparation and imaging. The work was supported by grants from the NIH to M.B.F. ( R01-NS083391 , R01-AG044113 ) and M.K.L. (R01-NS086074 , R01-NS092093 ) and from the NSF to D.G.O. ( DGE1144152 , DGE1745303 ).
Funding Information:
Fly stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537), the Vienna Drosophila Resource Center, H. Bellen, S. Bogdan, R. Dubreuil, C. Potter, T. Schwarz, and D. Williams were used in this study. We thank the Transgenic RNAi Project (TRiP) at Harvard Medical School (NIH-NIGMS R01GM084947) for making transgenic RNAi stocks. Monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biology, Iowa City, IA 52242. We thank Ms. Joyce Meints for technical assistance with mouse brain tissue processing. We acknowledge the Harvard Neurodiscovery Center Enhanced Neuroimaging Facility staff for assistance with confocal imaging and 3D reconstruction and the Harvard Center for Biological Imaging staff for insightful comments on super-resolution sample preparation and imaging. The work was supported by grants from the NIH to M.B.F. (R01-NS083391, R01-AG044113) and M.K.L. (R01-NS086074, R01-NS092093) and from the NSF to D.G.O. (DGE1144152, DGE1745303).
Publisher Copyright:
© 2017 Elsevier Inc.
Keywords
- actin
- mitochondria
- spectrin
- α-synuclein
- α-synucleinopathy