Tumor suppressor PALB2 maintains redox and mitochondrial homeostasis in the brain and cooperates with ATG7/autophagy to suppress neurodegeneration

The PALB2 tumor suppressor plays key roles in DNA repair and has been implicated in redox homeostasis. Autophagy maintains mitochondrial quality, mitigates oxidative stress and suppresses neurodegeneration. Here we show that Palb2 deletion in the mouse brain leads to mild motor deficits and that co-deletion of Palb2 with the essential autophagy gene Atg7 accelerates and exacerbates neurodegeneration induced by ATG7 loss. Palb2 deletion leads to elevated DNA damage, oxidative stress and mitochondrial markers, especially in Purkinje cells, and co-deletion of Palb2 and Atg7 results in accelerated Purkinje cell loss. Further analyses suggest that the accelerated Purkinje cell loss and severe neurodegeneration in the double deletion mice are due to excessive oxidative stress and mitochondrial dysfunction, rather than DNA damage, and partially dependent on p53 activity. Our studies uncover a role of PALB2 in mitochondrial homeostasis and a cooperation between PALB2 and ATG7/autophagy in maintaining redox and mitochondrial homeostasis essential for neuronal survival.

Author summary
PALB2 is a tumor suppressor in which inherited mutations increase the risk of breast, ovarian, pancreatic, and other cancers. It plays a critical role in DNA repair and promotes antioxidant gene expression. ATG7 is an essential factor for autophagy, an intracellular waste disposal and nutrient recycling process. Loss of autophagy function leads to accumulation of toxic wastes and damaged mitochondria, leading to oxidative stress and other problems in the cell. As neurons in the brain are particularly sensitive to oxidative stress and waste accumulation, loss of ATG7 or autophagy in the brain causes death of neurons and neurodegeneration. In this study, we found that loss of PALB2 in the brain led to oxidative stress accompanied by increased amount of functionally impaired mitochondria, and that combined loss of PALB2 and ATG7 caused accelerated and more severe neurodegeneration than did ATG7 loss alone. We further found that the exacerbated phenotype was mainly caused by excessive oxidative stress, rather than increased DNA damage. Our studies establish a new function of PALB2, i.e., mitochondrial regulation, provide additional insights into the function of ATG7 in the brain, and further underscore the role of oxidative stress in neuronal death and neurodegeneration.