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

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Hum Mol Genet. 2009 Sep 29.

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

Ferguson CJ, Lenk GM, Meisler MH.

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

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 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 CNS and demonstrate that mutations

affecting PI(3,5)P(2) can contribute to inclusion body disease,