p62/sequestosome-1 knockout delays neurodegeneration induced by Drp1 loss

Neurochemistry International
Tatsuya YamadaHiromi Sesaki

Abstract

Purkinje neurons, one of the largest neurons in the brain, are critical for controlling body movements, and the dysfunction and degeneration of these cells cause ataxia. Purkinje neurons require a very efficient energy supply from mitochondria because of their large size and extensive dendritic arbors. We have previously shown that mitochondrial division mediated by dynamin-related protein 1 (Drp1) is critical for the development and survival of Purkinje neurons. Drp1 deficiency has been associated with one of the major types of ataxia: autosomal recessive spastic ataxia of Charlevoix Saguenay. Using post-mitotic Purkinje neuron-specific Drp1 knockout (KO) in mice, we investigated the molecular mechanisms that mediate the progressive degeneration of Drp1-KO Purkinje neurons in vivo. In these Purkinje neurons, p62/sequestosome-1, a multi-functional adaptor protein that balances apoptotic cell death and cell survival, was recruited to large mitochondria resulting from unopposed fusion in the absence of mitochondrial division. To test the role of p62 in Drp1-deficient neurodegeneration, we created mice lacking both Drp1 and p62 and found that the additional loss of p62 significantly extended the survival of Purkinje neurons lackin...Continue Reading

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Citations

May 31, 2021·Free Radical Biology & Medicine·Lixi ShiShengbin Huang
Jun 22, 2021·The EMBO Journal·Guillermo López-DoménechJosef T Kittler
Aug 1, 2021·Biochimica Et Biophysica Acta. General Subjects·Koji Yamano, Waka Kojima

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