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

• Published in: Nature communications Vol. 13; no. 1; pp. 159 - 19
• Main Authors: Yang, Yun, Tapias, Victor, Acosta, Diana, Xu, Hui, Chen, Huanlian, Bhawal, Ruchika, Anderson, Elizabeth T., Ivanova, Elena, Lin, Hening, Sagdullaev, Botir T., Chen, Jianer, Klein, William L., Viola, Kirsten L., Gandy, Sam, Haroutunian, Vahram, Beal, M. Flint, Eliezer, David, Zhang, Sheng, Gibson, Gary E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/6; 13/1; 13/106; 13/51; 140/58; 147/28; 631/378/1689/1283; 631/45/2783; 82/51; 82/58; Abnormalities; Accumulation; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amino Acid Sequence; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animal models; Animals; Autopsy; Brain; Brain - metabolism; Brain - pathology; Case-Control Studies; Disease Models, Animal; Gene Expression Profiling; Glucose metabolism; Humanities and Social Sciences; Humans; Lysine; Metabolism; Mice; Mice, Transgenic; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; Neurodegenerative diseases; Pathogenesis; Plaque, Amyloid - genetics; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Plaques; Post-translation; Protein Aggregates; Protein Processing, Post-Translational; Protein turnover; Proteins; Proteolysis; Proteome - genetics; Proteome - metabolism; Proteomes; Science; Science (multidisciplinary); Succinic Acid - metabolism; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Transgenic mice; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27572-2

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. Succinylation is a metabolism-associated post-translational protein modification. Here the authors describe changes to the succinylation of proteins in the brain of individuals with Alzheimer’s disease.