Although the primary function of autophagy is the supply of amino acids as a response to starvation conditions in many organisms, recent studies suggested that basal autophagy, which occurs independently of nutrient stress, also plays an important role in maintaining cellular homeostasis, particularly in quiescent cells such as neurons. FIP200 (FAK family interacting protein of 200 KDa) was recently proposed as a mammalian counterpart of yeast Atg17 (autophagy-related 17) required for autophagosome initiation despite its different structure and sequence from Atg17. However, it remains unclear whether mammalian FIP200 regulates autophagy in vivo and the regulation is also involved in neuronal homeostasis and neurodegeneration. In this study, the results collected from the brain of which FIP200 was depleted by nestin-Cre showed that cerebellar degeneration and ataxia accompanied by progressive loss of Purkinje cells, swelling and degeneration of their axons, and spongiform degeneration in the cerebellum. Further analyses by conditional deletion of FIP200 using hGFAP-Cre and L7-Cre with complementary Cre expression in the cerebellum provided support for a Purkinje cell-autonomous function of FIP200 in the regulation of cerebellar degeneration. Consistent with a role of FIP200 in autophagy, observed progressive accumulation of abnormal ubiquitinated protein aggregates without any impairment of the ubiquitin-proteasome activity, increased apoptosis, and mitochondrial damage in Purkinje cells were found in the mutant mice. Lastly, the study demonstrated that deletion of TNF-R1 rescued both the loss of Purkinje cells and spongiform degeneration in FIP200 conditional KO mice. Together, these results provided compelling genetic evidence that FIP200 regulation of autophagy and TNFR1 signaling playscritical roles in the pathogenesis of neurodegenerative disorders in mammals.