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Human Molecular Genetics Advance Access originally published online on September 29, 2009
Human Molecular Genetics 2009 18(24):4868-4878; doi:10.1093/hmg/ddp460
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© The Author 2009. Published by Oxford University Press
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2

Cole J. Ferguson, Guy M. Lenk and Miriam H. Meisler*

Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA

* To whom correspondence should be addressed at: Department of Human Genetics, University of Michigan Medical School, 4909 Buhl, Ann Arbor, MI 48109-5618, USA. Tel: +1 7347635546; Fax: +1 7347639691; Email: meislerm{at}umich.edu

Received August 10, 2009; Accepted September 25, 2009

Mutations affecting the conversion of PI3P to the signaling lipid PI(3,5)P2 result in spongiform degeneration of mouse brain and are associated with the human disorders Charcot–Marie–Tooth disease and amyotrophic lateral sclerosis (ALS). We now report accumulation of the proteins LC3-II, p62 and LAMP-2 in neurons and astrocytes of mice with mutations in two components of the PI(3,5)P2 regulatory complex, Fig4 and Vac14. Cytoplasmic inclusion bodies containing p62 and ubiquinated proteins are present in regions of the mutant brain that undergo degeneration. Co-localization of p62 and LAMP-2 in affected cells indicates that formation or recycling of the autolysosome is impaired. These results establish a role for PI(3,5)P2 in autophagy in the mammalian central nervous system (CNS) and demonstrate that mutations affecting PI(3,5)P2 can contribute to inclusion body disease.


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