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

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.