Journal
HUMAN MOLECULAR GENETICS
Volume 18, Issue 24, Pages 4868-4878Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddp460
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Funding
- NIH [R01 GM24872]
- Medical Sciences Training Program [T32 GM07863]
- Training Program in Systems and Integrative Biology [T32 GM008322]
- Hartwell Foundation
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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.
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