Identification of genes that modify ataxin-1-induced neurodegeneration

ABSTRACT A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease1. Spinocerebellar ataxia type 1 (SCA1) is

one such disease—caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this

group of diseases, we have created a model system for SCA1 by expressing the full-length human _SCA1_ gene in _Drosophila_. Here we show that high levels of wild-type ataxin-1 can cause

degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers

highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers

that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other

neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE POLYGLUTAMINE PROTEIN ATXN2: FROM ITS MOLECULAR FUNCTIONS TO

ITS INVOLVEMENT IN DISEASE Article Open access 14 June 2024 PROGRESSIVE DEGENERATION IN A NEW _DROSOPHILA_ MODEL OF SPINOCEREBELLAR ATAXIA TYPE 7 Article Open access 21 June 2024 A

GGC-REPEAT EXPANSION IN _ZFHX3_ ENCODING POLYGLYCINE CAUSES SPINOCEREBELLAR ATAXIA TYPE 4 AND IMPAIRS AUTOPHAGY Article 29 April 2024 REFERENCES * Cummings, C. J. & Zoghbi, H. Y.

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Mancini for help with the confocal microscope; K.-W. Choi and members of his laboratory for help with the eye sections; C. Cummings for advice and insightful discussions; V. Brandt for

editorial help; M. Magarinos and P. Herrero for help with the initial fly screens; R. Davis and A. L. Beaudet for reading the manuscript; C. Cater, G. Rubin, D. Cribbs, R. Davis, T. Aigaki,

H. Steller, G. Pennetta, S. Parkhurst and the Bloomington Stock Center for fly strains; and M. Levine and R. Wharton for antibodies. This work was supported by a grant of the NIH to J.B.

J.B. is also grateful for initial support by the Banco Bilbao Vizcaya. M.L.N.-R. was supported by an HHMI postdoctoral fellowship for physicians. H.Y.Z. is a Howard Hughes Medical Institute

Investigator. AUTHOR INFORMATION Author notes * Pedro Fernandez-Funez, Maria Laura Nino-Rosales and Huda Y. Zoghbi: These authors contributed equally to this work AUTHORS AND AFFILIATIONS *

Department of Molecular and Human Genetics, Pedro Fernandez-Funez, Maria Laura Nino-Rosales, Beatrice de Gouyon, Wei-Chi She, James M. Luchak, Pedro Martinez, Maria Capovilla, Alanna McCall,

 Huda Y. Zoghbi & Juan Botas * Department of Pediatrics, Huda Y. Zoghbi * Program in Developmental Biology, Wei-Chi She, Huda Y. Zoghbi & Juan Botas * Howard Hughes Medical

Institute, Baylor College of Medicine, Houston, 77030, Texas, USA Huda Y. Zoghbi * Departamento de Biologia, Universidad Autonoma de Madrid, Madrid, 28049, Spain Enrique Turiegano, Jonathan

Benito & Inmaculada Canal * Institute of Human Genetics, University of Minnesota, Minneapolis, 55455 , Minnesota, USA Pamela J. Skinner & Harry T. Orr Authors * Pedro Fernandez-Funez

View author publications You can also search for this author inPubMed Google Scholar * Maria Laura Nino-Rosales View author publications You can also search for this author inPubMed Google

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Supplementary Information RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Fernandez-Funez, P., Nino-Rosales, M., de Gouyon, B. _et al._ Identification of

genes that modify ataxin-1-induced neurodegeneration . _Nature_ 408, 101–106 (2000). https://doi.org/10.1038/35040584 Download citation * Received: 16 June 2000 * Accepted: 04 October 2000

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