Autophagy is an intracellular self-digestion process that plays a critical role in maintaining neuronal homeostasis. PALB2 is a tumor suppressor protein essential for homologous recombination-based DNA repair, redox homeostasis and breast cancer suppression. We previously showed that deletion of Palb2 in the mouse mammary gland using Cre recombinase driven by the whey acid protein promoter (Wap-cre) led to mammary tumor development, which was delayed in a low-autophagy background. To further understand the role of autophagy in breast cancer development, we co-deleted the essential autophagy gene Atg7 together with Palb2 using Wap-cre. Surprisingly, Wap-cre-driven deletion of Atg7 resulted in neurodegeneration evidenced by motor deficits, and combined deletion of Palb2 and Atg7 led to a similar but much more severe phenotype so that the mice died before mammary tumor development. This was found to be due to a high level of 'leaky' expression of Wap-cre in the brain. Morphologic and immunohistochemical studies revealed that Atg7 deletion caused aberrant accumulation of p62, loss of Purkinje cell in the cerebellum, and progressive formation of inclusion bodies in neurons, Co-deletion of Palb2 with Atg7 significantly accelerated the Purkinje cell loss and inclusion body formation, and increased amount of apoptotic cells and necrotic cells. Electron microscopy further revealed a breakdown of myelin sheath and deformed synapse in Palb2f/f;Atg7f/f; Wap-cre mice. Mechanistically, we found markedly higher levels of DNA damage marker γH2AX and DNA oxidation marker 8-oxo-dG in both Palb2 single and Palb2/Atg7 double deletion brains compared with Atg7 single deletion brain. Taken together, these findings suggest that PALB2 plays an important role in neurons by preventing DNA damage and oxidative stress, and autophagy is required for the normal functioning and survival of neurons in the face of DNA damage and oxidative stress elicited by the loss of PALB2.