Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival

Veronika Redmann, Christopher A. Lamb, Seungmin Hwang, Robert C. Orchard, Sungsu Kim, Minoo Razi, Ashley Milam, Sunmin Park, Christine C. Yokoyama, Amal Kambal, Darren Kreamalmeyer, Marie K. Bosch, Maolei Xiao, Karen Green, Jungsu Kim, Shondra M. Pruett-Miller, David M. Ornitz, Paul M. Allen, Wandy L. Beatty, Robert E. SchmidtAaron Diantonio, Sharon A. Tooze, Herbert W. Virgin

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13 Scopus citations

Abstract

CLEC16A is in a locus genetically linked to autoimmune diseases including multiple sclerosis, but the function of this gene in the nervous system is unknown. Here we show that two mouse strains carrying independent Clec16a mutations developed neurodegenerative disease characterized by motor impairments and loss of Purkinje cells. Neurons from Clec16a-mutant mice exhibited increased expression of the autophagy substrate p62, accumulation of abnormal intra-axonal membranous structures bearing the autophagy protein LC3, and abnormal Golgi morphology. Multiple aspects of endocytosis, lysosome and Golgi function were normal in Clec16a-deficient murine embryonic fibroblasts and HeLa cells. However, these cells displayed abnormal bulk autophagy despite unimpaired autophagosome formation. Cultured Clec16a-deficient cells exhibited a striking accumulation of LC3 and LAMP-1 positive autolysosomes containing undigested cytoplasmic contents. Therefore Clec16a, an autophagy protein that is critical for autolysosome function and clearance, is required for Purkinje cell survival.

Original languageEnglish (US)
Article number23326
JournalScientific reports
Volume6
DOIs
StatePublished - Mar 18 2016

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    Redmann, V., Lamb, C. A., Hwang, S., Orchard, R. C., Kim, S., Razi, M., Milam, A., Park, S., Yokoyama, C. C., Kambal, A., Kreamalmeyer, D., Bosch, M. K., Xiao, M., Green, K., Kim, J., Pruett-Miller, S. M., Ornitz, D. M., Allen, P. M., Beatty, W. L., ... Virgin, H. W. (2016). Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival. Scientific reports, 6, [23326]. https://doi.org/10.1038/srep23326