Neural-specific Deletion of FIP200 Leads to Cerebellar Degeneration Caused by Increased Neuronal Death and Axon Degeneration

Chun-Chi Liang,Chenran Wang,Xu Peng,Boyi Gan,Jun-Lin Guan

doi:10.1074/jbc.m109.072389

Chun-Chi Liang, Chenran Wang + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m109.072389

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Abstract

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.

Highlights

FIP200 (FAK family-interacting protein of 200 kDa)4 was initially identified as a protein that interacts with and inhibits the kinases Pyk2 and FAK [9]
Our results reveal a role of FIP200 in the regulation of neuronal homeostasis, and deletion of FIP200 led to cerebellar degeneration, which is caused by axon degeneration and loss of Purkinje cells as well as increased apoptosis of cerebellar granule cells
Ablation of FIP200 in the Neuronal Precursors Leads to Severe Neurological Defects in Mice—To study the potential role of FIP200 in the central nervous system, the floxed FIP200 (FIP200f/f) mice, in which exons 4 and 5 of FIP200 gene are flanked by two loxP sequences [20], were crossed with the nestin-Cre transgenic mice, which express Cre recombinase in neural precursors from embryonic day 10.5 (E10.5) [22,23,24]

Summary

Introduction

FIP200 (FAK family-interacting protein of 200 kDa)4 was initially identified as a protein that interacts with and inhibits the kinases Pyk2 and FAK [9]. Deletion of FIP200 Results in Progressive Neuronal Loss, Spongiosis, and Neurite Degeneration in the Cerebellum—To study the cerebellum defects in FIP200f/f;nestin-Cre mice, histological analyses were performed on cerebella of control and mutant mice at various stages of postnatal development.

Results

Conclusion