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- W3215698528 abstract "Abstract Background: Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles (NFT) is a defining feature of Alzheimer’s Disease (AD), with specific epitopes such as Tau pT231 emerging early in the development of tau pathology. Previously, we demonstrated that a phosphomimetic mutant (T231E) of human tau drove the loss of neuronal function and structural integrity with age in a novel C. elegans single-copy gene insertion AD model. A critical finding was that T231E, unlike wild type tau, suppressed oxidative stress-induced mitochondrial autophagy, or mitophagy. Regulation of mitochondrial morphology by fission is important for mitophagy, which has been reported to be dysregulated by AD-relevant tau species. Dynamin Related Protein 1 (Drp1) is a GTPase that plays a central role in mediating mitochondrial fission, and its altered function may contribute to AD pathogenesis. Methods: Genetically-encoded fluorescent biosensors and dynamic imaging approaches were combined with a genomic drp-1(-) loss-of-function and transgenic tau mutants to derive a comprehensive in vivo analysis of age-associated changes in mitochondria and mitolysosome (ML) morphology, abundance, neurite trafficking, and stress-induced mitophagy. Results: Strain expressing disease-associated PTM mimetic Tau T231E demonstrated a surprisingly selective effect on ML development and trafficking, with no effect on lysosomes or autolysosomes, and a subtle effect on mitochondria that was apparent mainly in older animals. Unexpectedly, we found that drp-1(-) mutants mount a robust mitophagy response to oxidative stress, consistent with recent observations that adaptive mitophagy may occur independent of the canonical DRP1 pathway. Moreover, T231E continued to suppress oxidative stress-induced mitophagy in the drp-1(-) background. Conclusions: Our C. elegans single-copy gene insertion model unveils multiple levels of selectivity – phenotypic selectivity for mutations that mimic pathologic tauopathy-associated PTM and physiologic selectivity for organelles that contain damaged mitochondria. In addition, our novel findings provide compelling support for DRP1-independent mechanisms playing a pivotal role in regulating mitochondrial dynamics and function in the context of AD-relevant tau species and age-associated stress." @default.
- W3215698528 created "2021-12-06" @default.
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- W3215698528 date "2021-11-29" @default.
- W3215698528 modified "2023-10-17" @default.
- W3215698528 title "Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer’s Disease Relevant Tau Modification in a Novel C. elegans Model" @default.
- W3215698528 doi "https://doi.org/10.21203/rs.3.rs-1096882/v1" @default.
- W3215698528 hasPublicationYear "2021" @default.
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