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.
Highlights
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
Analysis of two cohorts each consisting of brain tissues from five controls and five AD patients was performed to maximize the precision and reproducibility of the succinylome (Fig. 1a, b) and the proteome (Fig. 1c, d) determinations
Over 90% of succinylated peptides being identified were equivalent to 0 miss-cleavage and 10% contained 1 miss-cleavage site in our data, which is consistent with what we observed in our regular global proteomics
Summary
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. We show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. 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. Misfolded deposits of the amyloid beta peptide (Aβ)[1,2] and the microtubule-associated protein tau (MAPT)[3] are pivotal pathological features in Alzheimer’s disease (AD), wherein reduced brain regional glucose metabolism and synaptic density are correlated with the development of clinical cognitive dysfunction[4]. The interactions of lysine succinylation and acetylation play important roles in metabolic pathways[14]. The results suggest that succinylation may link AD-related metabolic deficits to structural, functional, and pathological alterations involving APP and tau
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