Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo

• DOI: 10.1016/j.neuron.2012.06.026
• Publication Date: 2012-08-22T15:15:18Z
• Authors: Brian DuBoff; Jürgen Götz; Mel B. Feany
• Keywords: 2800 Neuroscience; Dynamins; 0301 basic medicine; Cytoplasm; Dominant optic atrophy; Mitochondrial-function; Neuroscience(all); Green Fluorescent Proteins; Cell Cycle Proteins; GTP Phosphohydrolases; Animals, Genetically Modified; 03 medical and health sciences; GTP-Binding Proteins; In Situ Nick-End Labeling; Animals; Drosophila Proteins; Humans; Gelsolin; Analysis of Variance; Cell Death; Actins; Dynamin-related protein; Alzheimers-Disease brain; ATP Synthetase Complexes; Cytoskeletal Proteins; Disease Models, Animal; Gene Expression Regulation; Drosophila

Mitochondrial abnormalities have been documented in Alzheimer's disease and related neurodegenerative disorders, but the causal relationship between mitochondrial changes and neurodegeneration, and the specific mechanisms promoting mitochondrial dysfunction, are unclear. Here, we find that expression of human tau results in elongation of mitochondria in both Drosophila and mouse neurons. Elongation is accompanied by mitochondrial dysfunction and cell cycle-mediated cell death, which can be rescued in vivo by genetically restoring the proper balance of mitochondrial fission and fusion. We have previously demonstrated that stabilization of actin by tau is critical for neurotoxicity of the protein. Here, we demonstrate a conserved role for actin and myosin in regulating mitochondrial fission and show that excess actin stabilization inhibits association of the fission protein DRP1 with mitochondria, leading to mitochondrial elongation and subsequent neurotoxicity. Our results thus identify actin-mediated disruption of mitochondrial dynamics as a direct mechanism of tau toxicity in neurons in vivo.