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Hum Mol Genet. 2009 Dec 15;18(24):4868-78. doi: 10.1093/hmg/ddp460. Epub 2009 Sep 29.

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

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  • 1Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.

Abstract

Mutations affecting the conversion of PI3P to the signaling lipid PI(3,5)P(2) 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)P(2) 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)P(2) in autophagy in the mammalian central nervous system (CNS) and demonstrate that mutations affecting PI(3,5)P(2) can contribute to inclusion body disease.

PMID:
19793721
[PubMed - indexed for MEDLINE]
PMCID:
PMC2778378
Free PMC Article
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