Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease

Yun Yang, Victor Tapias, Diana Acosta, Hui Xu, Huanlian Chen, Ruchika Bhawal, Elizabeth T. Anderson, Elena Ivanova, Hening Lin, Botir T. Sagdullaev, Jianer Chen, William L. Klein, Kirsten L. Viola, Sam Gandy, Vahram Haroutunian, M. Flint Beal, David Eliezer, Sheng Zhang and Gary E. Gibson ()
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Yun Yang: College of Medicine, Jiaxing University
Victor Tapias: Weill Cornell Medicine
Diana Acosta: Weill Cornell Medicine
Hui Xu: Weill Cornell Medicine
Huanlian Chen: Weill Cornell Medicine
Ruchika Bhawal: Cornell University
Elizabeth T. Anderson: Cornell University
Elena Ivanova: Imaging Core, Burke Neurological Institute
Hening Lin: Cornell University
Botir T. Sagdullaev: Weill Cornell Medicine
Jianer Chen: College of Medicine, Jiaxing University
William L. Klein: Northwestern University
Kirsten L. Viola: Northwestern University
Sam Gandy: Icahn School of Medicine at Mount Sinai
Vahram Haroutunian: Department of Psychiatry Icahn School of Medicine at Mount Sinai
M. Flint Beal: Weill Cornell Medicine
David Eliezer: Weill Cornell Medicine
Sheng Zhang: Cornell University
Gary E. Gibson: Weill Cornell Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.

Date: 2022
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DOI: 10.1038/s41467-021-27572-2

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