@article{f599287454254a378e59f03855ed5f9e,
title = "Biotin rescues mitochondrial dysfunction and neurotoxicity in a tauopathy model",
abstract = "Mitochondrial and metabolic dysfunction are often implicated in neurological disease, but effective mechanism-based therapies remain elusive. We performed a genome-scale forward genetic screen in a Drosophila model of tauopathy, a class of neurodegenerative disorders characterized by the accumulation of the protein tau, and identified manipulation of the B-vitamin biotin as a potential therapeutic approach in tauopathy. We show that tau transgenic flies have an innate biotin deficiency due to tau-mediated relaxation of chromatin and consequent aberrant expression of multiple biotin-related genes, disrupting both carboxylase and mitochondrial function. Biotin depletion alone causes mitochondrial pathology and neurodegeneration in both flies and human neurons, implicating mitochondrial dysfunction as a mechanism in biotin deficiency. Finally, carboxylase biotin levels are reduced in mammalian tauopathies, including brains of human Alzheimer{\textquoteright}s disease patients. These results provide insight into pathogenic mechanisms of human biotin deficiency, the resulting effects on neuronal health, and a potential therapeutic pathway in the treatment of tau-mediated neurotoxicity.",
keywords = "Biotin, Drosophila, Mitochondria, Screen, Tau",
author = "Lohr, {Kelly M.} and Bess Frost and Clemens Scherzer and Feany, {Mel B.}",
note = "Funding Information: ACKNOWLEDGMENTS. Fly stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537), the Vienna Drosophila Resource Center, and Drs. D. Williams, A. Vincent, M. Crozatier, T. Schwarz, and N. Bonini were used in this study. We thank the Transgenic RNAi Project at the Harvard Medical School (NIH National Institute of General Medical Sciences R01GM084947) for making transgenic RNAi stocks and the Harvard Medical School Neuroimaging facility (NIH NINDS P30NS072030) for assistance with imaging. Monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development (NICHD of the NIH) and maintained by the Department of Biology, University of Iowa, and the University of California, Davis/NIH NeuroMab Facility. This work was supported by NIH National Institute on Aging (NIA) Grant F32NS100308 (to K.M.L.) and NIH NIA Grants R01 AG044113 and R01 AG057331 (to M.B.F. and C.S.). Funding Information: Fly stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537), the Vienna Drosophila Resource Center, and Drs. D. Williams, A. Vincent, M. Crozatier, T. Schwarz, and N. Bonini were used in this study. We thank the Transgenic RNAi Project at the Harvard Medical School (NIH National Institute of General Medical Sciences R01GM084947) for making transgenic RNAi stocks and the Harvard Medical School Neuroimaging facility (NIH NINDS P30NS072030) for assistance with imaging. Monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the National Institute of Child Health and Human Development (NICHD of the NIH) and maintained by the Department of Biology, University of Iowa, and the University of California, Davis/NIH NeuroMab Facility. This work was supported by NIH National Institute on Aging (NIA) Grant F32NS100308 (to K.M.L.) and NIH NIA Grants R01 AG044113 and R01 AG057331 (to M.B.F. and C.S.). Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = dec,
doi = "10.1073/PNAS.1922392117",
language = "English (US)",
volume = "117",
pages = "33608--33618",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "52",
}