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bioRxiv · 10.1101/2023.08.10.552882

Ubiquitin phosphorylation accelerates protein aggregation and promotes neurodegeneration in the aging brain

Chen, C.·Yi, H.-W.·Zhang, Y.·Wang, T.·Gao, T.-Y.·Lou, Z.-L.·Wei, T.-F.·Lu, Y.-B.·Li, T.-T.·Zhang, W.-P.·Tang, C.
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Abstract

Ser65-phosphorylated ubiquitin (pUb) was found elevated in neurons of aged and neurodegenerative brains. Yet little is known whether a causative link exists between pUb level and brain aging. Here we show that the knockout of pink1, a Ub kinase, abolished pUb elevation and decelerated protein aggregation in aged mouse brains and cells with proteasomal inhibition. Conversely, over-expression of PINK1 but not the kinase-dead version increased the pUb level and accelerated protein aggregation by suppressing of proteasomal degradation. Furthermore, PINK1 over-expression in mouse hippocampus neurons increased pUb level and protein aggregation, slowly leading to mitochondrial injury, neurodegeneration, and cognitive impairment. Notably, the neuronal damages induced by PINK1 were rescued by the dominant negative Ub/S65A mutant, while Ub/S65E phosphomimetic mutant caused neuronal death. Together, an incidental increase of Ub phosphorylation can progressively and cumulatively cause the decline of Ub-dependent proteasomal activity, consequenting promotes neurodegeneration in the aging brain.

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Chen, C., Yi, H.-W., Zhang, Y., Wang, T., Gao, T.-Y., Lou, Z.-L., Wei, T.-F., Lu, Y.-B., Li, T.-T., Zhang, W.-P., Tang, C.. 2023-08-12. Ubiquitin phosphorylation accelerates protein aggregation and promotes neurodegeneration in the aging brain. https://doi.org/10.1101/2023.08.10.552882

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