Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration.
FIP200 (FAK family-interacting protein of 200 kDa) is a conserved protein recently identified as a potential mammalian counterpart of yeast autophagy protein Atg17. However, it remains unknown whether mammalian FIP200 regulates autophagy in vivo. Here we show that neural-specific deletion of FIP200 resulted in cerebellar degeneration accompanied by progressive neuronal loss, spongiosis, and neurite degeneration in the cerebellum. Furthermore, deletion of FIP200 led to increased apoptosis in cerebellum as well as accumulation of ubiquitinated protein aggregates without any deficiency in proteasome catalytic functions. We also observed an increased p62/SQSTM1 accumulation in the cerebellum and reduced autophagosome formation as well as accumulation of damaged mitochondria in the mutant mice. Lastly, analysis of cerebellar neurons in vitro showed reduced JNK activation and increased susceptibility to serum deprivation-induced apoptosis in cerebellar neurons from the mutant mice. Taken together, these results provide strong genetic evidence for a role of FIP200 in the regulation of neuronal homeostasis through its function in autophagy in vivo.
Liang
Chun-Chi
CC
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Wang
Chenran
C
Peng
Xu
X
Gan
Boyi
B
Guan
Jun-Lin
JL
D000818:Animals; D017209:Apoptosis; D000071183:Autophagy-Related Proteins; D001369:Axons / Q000473:pathology*; D016923:Cell Death; D002531:Cerebellum / Q000378:metabolism; D017353:Gene Deletion; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016501:Neurites / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010588:Phagosomes / Q000378:metabolism
D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; C428743:Rb1cc1 protein, mouse