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.
Ferguson
Cole J
CJ
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA.
Lenk
Guy M
GM
Meisler
Miriam H
MH
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology*; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005420:Flavoproteins / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000172:deficiency* / Q000235:genetics; D000072180:Phosphoinositide Phosphatases; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D005420:Flavoproteins; C490981:Gtf2h1 protein, mouse; D052119:Lysosomal-Associated Membrane Protein 2; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D018129:Phosphatidylinositol Phosphates; D014157:Transcription Factors; D025801:Ubiquitin; C106336:phosphatidylinositol 3,5-diphosphate; D051758:Transcription Factor TFIIH; C522216:Fig4 protein, mouse; D000072180:Phosphoinositide Phosphatases