Selective disruption of Drp1-independent mitophagy and mitolysosome trafficking by an Alzheimer’s disease relevant tau modification in a novelCaenorhabditis elegansmodel

Genetics, Journal Year: 2022, Volume and Issue: 222(1)

Published: Aug. 2, 2022

Abstract Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles is a defining feature Alzheimer’s disease, with Tau pT231 being an early harbinger pathology. Previously, we demonstrated that expressing single genomic copy human phosphomimetic mutant (T231E) in Caenorhabditis elegans drove age-dependent neurodegeneration. A critical finding was T231E, unlike wild-type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, used dynamic imaging approaches to analyze T231E-associated changes mitochondria mitolysosome morphology, abundance, trafficking, mitophagy as function mitochondrial fission mediator dynamin-related protein 1, which has been interact hyper contribute disease pathogenesis, well Pink1, well-recognized quality control works together Parkin support T231E impacted both neurite trafficking exquisite selectivity, sparing macroautophagy lysosome autolysosome trafficking. Both oxidative-stress-induced the ability suppress it were independent drp-1, but at least partially dependent on pink-1. Organelle more complicated, drp-1 pink-1 mutants exerting effects, generally supported idea phenotype greater physiologic impact T231E. Collectively, our results refine mechanistic pathway through causes neurodegeneration, demonstrating pathologic selectivity for mutations mimic tauopathy-associated post-translational modifications, organelles contain damaged mitochondria, molecular 1-independent, Pink1-dependent, perhaps adaptive,

Language: Английский

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Clemastine fumarate attenuates tauopathy and meliorates cognition in hTau mice via autophagy enhancement

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 123, P. 110649 - 110649

Published: July 24, 2023

Language: Английский

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HSPB8 up-regulation alleviates cognitive dysfunction in a mouse model of sepsis-associated encephalopathy

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 122, P. 110448 - 110448

Published: July 1, 2023

Language: Английский

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Endogenous PTEN-induced kinase 1 regulates dendritic architecture and spinogenesis

Journal of Neuroscience, Journal Year: 2022, Volume and Issue: unknown, P. JN - 22

Published: Sept. 7, 2022

Mutations in PTEN-induced kinase 1 (PINK1) contribute to autosomal recessive Parkinson9s disease with cognitive and neuropsychiatric comorbidities. Disturbances dendritic spine architecture are hallmarks of neurodegenerative conditions, but little is known the impact PINK1 on these structures. We used Pink1^−/− mice study role endogenous regulating architecture, density, maturation. cortical neurons unknown sex showed decreased arborization, affecting both apical basal arbors. Dendritic simplification was primarily driven by diminished branching smaller effects branch lengths. reduced density a shift morphology favor filopodia at expense mushroom spines. Electrophysiology revealed significant reductions miniature EPSC (mEPSC) frequency neurons, consistent observation numbers. Transfecting human rescued changes thin, stubby, densities, mEPSC frequency. Diminished also observed Golgi–Cox stained adult male brains. Western blot brains either phosphorylation NSFL1 cofactor p47, an indirect target PINK1. Transfection phosphomimetic p47 plasmid thin/stubby partial rescue spines, implicating for PINK1-regulated dendrite development. These findings suggest that PINK1-dependent synaptodendritic alterations may risk and/or pathologies PINK1-mutated families. SIGNIFICANCE STATEMENT Loss function has been implicated familial sporadic diseases. Yet surprisingly loss fine structure neurons. Neurons receive excitatory synaptic signals along complex network projections form tree, largely tiny protrusions called studied brain tissues from lacking discovered deficiency causes striking associated input reversed reintroducing or one its downstream mediators into PINK1-deficient mouse indicating conserved function, whose processes.

Language: Английский

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The Critical Role of Autophagy and Phagocytosis in the Aging Brain

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 26(1), P. 57 - 57

Published: Dec. 25, 2024

As the organism ages, there is a decline in effective energy supply, and this retards ability to elaborate new proteins. The consequences of are especially marked gradual brain function. senescence cells their constituent organelles ultimately cause aging entire nervous system. What less immediately obvious that also accompanied by failure catabolic events lead removal non-functional ineffective subcellular components. non-working cellular elements within essential order allow appearance fresh with full range capacities. Thus, maintenance operative mechanisms for dispersal failed tissue components important, its diminished capacity significant contributory factor onset progression age-related neurological disorder. This report discusses underlying autophagy phagocytosis how these can be adversely modulated as proceeds. means which recycling may reinstated aged considered.

Language: Английский

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