Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease. Academic Article uri icon

Overview

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.

publication date

  • January 10, 2022

Research

keywords

  • Alzheimer Disease
  • Amyloid beta-Protein Precursor
  • Plaque, Amyloid
  • Protein Processing, Post-Translational
  • Succinic Acid
  • tau Proteins

Identity

PubMed Central ID

  • PMC8748865

Scopus Document Identifier

  • 85122850997

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-27572-2

PubMed ID

  • 35013160

Additional Document Info

volume

  • 13

issue

  • 1