# Disruption of Mitochondrial Dynamics in Tauopathy

 Title: Disruption of Mitochondrial Dynamics in Tauopathy Author: DuBoff, Brian Michael Citation: DuBoff, Brian Michael. 2011. Disruption of Mitochondrial Dynamics in Tauopathy. Doctoral dissertation, Harvard University. Access Status: Full text of the requested work is not available in DASH at this time (“dark deposit”). For more information on dark deposits, see our FAQ. Full Text & Related Files: DuBoff_gsas.harvard_0084L_10021.pdf (5.695Mb; PDF) Abstract: Alzheimer’s disease (AD) is characterized pathologically by proteinaceous aggregates composed primarily of amyloid $$\beta (A \beta)$$ and tau. Diseases characterized by abnormal deposition of tau are collectively termed “tauopathies.” $$A \beta$$ acts upstream of tau in the AD pathogenesis pathway, but tau expression is required for the neurodegenerative effects of $$A \beta$$. Mitochondrial abnormalities have been documented in Alzheimer’s disease and related tauopathies, but the causal relationship between mitochondrial changes and neurodegeneration, as well as specific mechanisms promoting mitochondrial dysfunction, are unclear. Mitochondrial morphology is regulated by fission and fusion events within and between individual mitochondria, and misregulation of this process has been observed in several neurodegenerative diseases. The contribution of mitochondrial dynamics to the pathogenesis of Alzheimer’s disease and tauopathy has not yet been determined. We have found that expression of tau promotes elongation of mitochondria in Drosophila and vertebrate neurons. Elongation is followed by mitochondrial dysfunction, aberrant cell cycle reactivation, and cell death, which can be rescued in vivo by genetically restoring the proper balance of mitochondrial fission and fusion. Tau induces mitochondrial elongation by inhibiting mitochondrial localization of DRP1, the primary effector of fission. We have previously demonstrated that direct tau-mediated stabilization of filamentous (F)-actin is critical for neurotoxicity. Here we show that actin stabilization is responsible for the mislocalization of DRP1 following tau expression. Additionally, we identify regulatory roles for F-actin and myosin II in DRP1 localization. Similarly to overexpression of human tau, loss of endogenous Drosophila tau (dtau) induces mitochondrial elongation, but through distinct mechanisms. Expression of human $$A \beta$$in Drosophila induces mitochondrial fragmentation and neuronal toxicity, which are reversed by depletion of dtau. Together, we demonstrate that human disease-associated tau induces neurotoxicity through disruption of mitochondrial dynamics, which can be mediated by enhanced actin stabilization. We also observe a novel role for dtau in the regulation of mitochondrial dynamics, a function critical to the ability of endogenous tau to mediate the effects of $$A \beta$$. These findings offer new insights into the contribution of mitochondrial dysfunction to AD and tauopathy, and highlight the emerging role of mitochondrial dynamics in the pathogenesis of neurodegenerative disease. Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10276000 Downloads of this work: