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

Autor: Huo Y; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., Sawant A; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America., Tan Y; Stomatological Hospital of Guangzhou Medical University, Guangzhou, P.R. China., Mahdi AH; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., Li T; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., Ma H; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., Bhatt V; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., Yan R; Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America.; RWJMS Institute for Neurological Therapeutics, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., Coleman J; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., Dreyfus CF; Rutgers School of Environmental and Biological Sciences, New Brunswick, New Jersey, United States of America., Guo JY; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America.; Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey, United States of America., Mouradian MM; Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America.; RWJMS Institute for Neurological Therapeutics, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America., White E; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America., Xia B; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2022 Apr 11; Vol. 18 (4), pp. e1010138. Date of Electronic Publication: 2022 Apr 11 (Print Publication: 2022).
DOI: 10.1371/journal.pgen.1010138
Abstrakt: 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.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EW is a founder of Vescor Therapeutics and a stockholder of Forma Therapeutics. MMM holds patents and is a founder of MentiNova, Inc. None of the above relates to the subject matter of this manuscript.
Databáze: MEDLINE
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