Succinylation Links Metabolic Reductions to Amyloid and Tau Pathology

Abstract

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.

The human brain acetylome reveals that decreased acetylation of mitochondrial proteins associates with Alzheimer's disease

“…Recent exhaustive studies of the human proteome in a different brain region demonstrate extensive AD related changes in protein levels. Our studies demonstrate that protein levels alone do not reflect the complexity of the changes, since functionally important changes in PTMs also occur, including succinylation (Yang et al, 2019) and acetylation.…”

“…All control subjects had test scores in the normal range, and neuropathologic evaluation of control brains revealed only age‐associated histopathologic alterations. The number of samples required was estimated from previous studies (Yang et al., 2019).…”

“…The protein extraction protocol and tryptic digestion were identical to our previous publications (Yang et al., 2019).…”

“…The nano‐LC‐MS/MS analysis was carried out using an Orbitrap Fusion (Thermo‐Fisher Scientific) as described previously (Yang et al., 2019).…”

Evidence for a Negative Correlation between Human Reactive Enamine-Imine Intermediate Deaminase A (RIDA) Activity and Cell Proliferation Rate: Role of Lysine Succinylation of RIDA

“…hRIDA contains 8 lysine residues, four of them are succinylated [ 32 ]. Of these, three lysine residues (K97, K101 and K117) are located near the interface of two monomers.…”