Tau phosphorylation and OPA1 proteolysis are unrelated events: Implications for Alzheimer's Disease

Biochim Biophys Acta Mol Cell Res. 2021 Nov;1868(12):119116. doi: 10.1016/j.bbamcr.2021.119116. Epub 2021 Aug 13.

Abstract

The neuropathological hallmarks of Alzheimer's Disease are plaques and neurofibrillary tangles. Yet, Alzheimer's is a complex disease with many contributing factors, such as energy-metabolic changes, which have been documented in autopsy brains from individuals with Alzheimer's and animal disease models alike. One conceivable explanation is that the interplay of age-related extracellular and intracellular alterations pertaining to Alzheimer's, such as cerebrovascular changes, protein aggregates and inflammation, evoke a mitochondrial response. However, it is not clear if and how mitochondria can contribute to Alzheimer's pathophysiology. This study focuses on one particular aspect of this question by investigating the functional interaction between the microtubule-associated protein tau and the mitochondrial inner membrane fusion machinery, which shows alterations in Alzheimer's brains. OPA1 is an essential inner membrane-fusion protein regulated by the two membrane proteases OMA1 and YME1L1. Assessment of OPA1 proteolysis-usually found in dividing mitochondria-and posttranslational tau modifications in mouse and human neuroblastoma cells under different experimental conditions clarified the relationship between these two pathways: OPA1 hydrolysis and phosphorylation or dephosphorylation of tau may coincide, but are not causally related. OPA1 cleavage did not alter tau's phosphorylation pattern. Conversely, tau's phosphorylation state did not induce nor correlate with OPA1 proteolysis. These results irrefutably demonstrate that there is no direct functional interaction between posttranslational tau modifications and the regulation of the OMA1-OPA1 pathway, which implies a common root cause modulating both pathways in Alzheimer's.

Keywords: Alzheimer's; Fusion.; Mitochondria; OMA1; Tau hyperphosphorylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism*
  • Cell Line, Tumor
  • GTP Phosphohydrolases / metabolism*
  • HEK293 Cells
  • Humans
  • Metalloendopeptidases / metabolism
  • Mitochondria / metabolism
  • Phosphorylation
  • Proteolysis*
  • tau Proteins / metabolism*

Substances

  • MAPT protein, human
  • tau Proteins
  • Metalloendopeptidases
  • molecule metalloprotease-related protein-1, human
  • GTP Phosphohydrolases
  • OPA1 protein, human