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

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.

• Authors: Marcel V Alavi
• Journal: Biochimica et biophysica acta. Molecular cell research (Biochim Biophys Acta Mol Cell Res) Vol. 1868 Issue 12 Pg. 119116 (11 2021) ISSN: 1879-2596 [Electronic] Netherlands
• PMID: 34400172 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

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

Topics

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