RRC ID 76178
Author Guha S, Cheng A, Carroll T, King D, Koren SA, Swords S, Nehrke K, Johnson GVW.
Title Selective disruption of Drp1-independent mitophagy and mitolysosome trafficking by an Alzheimer's disease relevant tau modification in a novel Caenorhabditis elegans model.
Journal Genetics
Abstract Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles is a defining feature of Alzheimer's disease, with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in Caenorhabditis elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild-type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator dynamin-related protein 1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to Alzheimer's disease pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and mitolysosome neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress-induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for dynamin-related protein 1-independent, Pink1-dependent, perhaps adaptive, and mitophagy.
Volume 222(1)
Published 2022-8-30
DOI 10.1093/genetics/iyac104
PII 6653303
PMID 35916724
PMC PMC9434186
MeSH Alzheimer Disease* / genetics Alzheimer Disease* / pathology Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / metabolism* Dynamins / genetics Dynamins / metabolism* Dynamins / pharmacology Humans Mitophagy* / physiology Protein Kinases / genetics Ubiquitin-Protein Ligases / genetics
Resource
C.elegans tm1108