PT  - JOURNAL ARTICLE
AU  - Yun Yang
AU  - Victor Tapias
AU  - Diana Acosta
AU  - Hui Xu
AU  - Huanlian Chen
AU  - Ruchika Bhawal
AU  - Elizabeth Anderson
AU  - Elena Ivanova
AU  - Hening Lin
AU  - Botir T. Sagdullaev
AU  - William L. Klein
AU  - Kirsten L. Viola
AU  - Sam Gandy
AU  - Vahram Haroutunian
AU  - M. Flint Beal
AU  - David Eliezer
AU  - Sheng Zhang
AU  - Gary E. Gibson
TI  - Succinylation Links Metabolic Reductions to Amyloid and Tau Pathology
AID  - 10.1101/764837
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 764837
4099  - http://biorxiv.org/content/early/2019/09/16/764837.short
4100  - http://biorxiv.org/content/early/2019/09/16/764837.full
AB  - Abnormalities in glucose metabolism and misfolded protein deposits composed of the amyloid-β peptide (Aβ) and tau are the three most common neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship(s) to the disease process or to each other largely remains unclear. In this report, the first human brain quantitative lysine succinylome together with a global proteome analysis from controls and patients reveals that lysine succinylation contributes to these three key AD-related pathologies. Succinylation, a newly discovered protein post-translational modification (PTM), of multiple proteins, particularly mitochondrial proteins, declines with the progression of AD. In contrast, amyloid precursor protein (APP) and tau consistently exhibit the largest AD-related increases in succinylation, occurring at specific sites in AD brains but never in controls. Transgenic mouse studies demonstrate that succinylated APP and succinylated tau are detectable in the hippocampus concurrent with Aβ assemblies in the oligomer and insoluble fiber assembly states. Multiple biochemical approaches revealed that succinylation of APP alters APP processing so as to promote Aβ accumulation, while succinylation of tau promotes its aggregation and impairs its microtubule binding ability. Succinylation, therefore, is the first single PTM that can be added in parallel to multiple substrates, thereby promoting amyloidosis, tauopathy, and glucose hypometabolism. These data raise the possibility that, in order to show meaningful clinical benefit, any therapeutic and/or preventative measures destined for success must have an activity to either prevent or reverse the molecular pathologies attributable to excess succinylation.