Autophagy, aging, and age-related neurodegeneration

Neuron, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance toxic proteins, proinflammatory molecules, dysfunctional organelles. inhibition also induces neuronal glial senescence, phenomenon occurs with increasing age non-diseased brains as well response to stresses. However, aging mutations impair autophagy. This creates potentially detrimental feedback loop whereby accumulation these disease-associated impairs their autophagic clearance, facilitating further aggregation. Thus, understanding how interacts aging, neurodegenerative diseases temporal, cellular, genetic context important for future clinical application autophagy-modulating therapies neurodegeneration.

Language: Английский

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Neuronal Autophagy: Regulations and Implications in Health and Disease

Cells, Journal Year: 2024, Volume and Issue: 13(1), P. 103 - 103

Published: Jan. 4, 2024

Autophagy is a major degradative pathway that plays key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed double-membrane autophagosome fuses with lysosomes, orchestrated by complex cascade events. has particularly strong impact on nervous system, mutations core cause numerous neurological diseases. We first review regulation autophagy, from biogenesis to lysosomal degradation associated neurodevelopmental/neurodegenerative disorders. then describe how this process specifically regulated axon somatodendritic compartment it altered In particular, we present neuronal specificities spatial control biogenesis, close relationship maturation axonal transport, synaptic activity. Finally, discuss functions autophagy during development adulthood.

Language: Английский

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Synaptic vesicle proteins and ATG9A self-organize in distinct vesicle phases within synapsin condensates

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 28, 2023

Abstract Ectopic expression in fibroblasts of synapsin 1 and synaptophysin is sufficient to generate condensates vesicles highly reminiscent synaptic vesicle (SV) clusters with liquid-like properties. Here we show that unlike synaptophysin, other major integral SV membrane proteins fail form synapsin, but co-assemble into the formed by this ectopic system. Another protein, ATG9A, undergoes activity-dependent exo-endocytosis at synapses, raising questions about relation ATG9A traffic SVs. We find both nerve terminals does not synaptophysin-positive localizes on a distinct class also assembles phase. Our findings suggest differential sorting relative point dual role controlling clustering synapses SVs vesicles.

Language: Английский

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Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112231 - 112231

Published: March 1, 2023

Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson's disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate mechanisms through which deficiency and clathrin-uncoating deficits lead PD. KO display cardinal features PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, neuroinflammation. Significantly, treatment with L-DOPA ameliorated deficits. Unbiased proteomic neurochemical analyses brains indicated dopamine dyshomeostasis. We validated these findings by demonstrating slower reuptake kinetics vivo, an effect associated transporter misrouting into axonal membrane deformities dorsal striatum. Defective SV protein sorting elevated autophagy also contribute ineffective sequestration compartmentalization, ultimately leading neurodegeneration. This study provides insights how endocytosis vulnerability pathogenesis

Language: Английский

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EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

Neuron, Journal Year: 2023, Volume and Issue: 111(9), P. 1402 - 1422.e13

Published: Feb. 23, 2023

Neuronal activity causes use-dependent decline in protein function. However, it is unclear how this coupled to local quality control mechanisms. We show Drosophila that the endocytic Endophilin-A (EndoA) connects activity-induced calcium influx synaptic autophagy and neuronal survival a Parkinson disease-relevant fashion. Mutations disordered loop, including disease-risk mutation, render EndoA insensitive stimulation affect dynamics: when more flexible, its mobility membrane nanodomains increases, making available for autophagosome formation. Conversely, rigid, reduces, blocking stimulation-induced autophagy. Balanced required dopagminergic neuron survival, variant human ENDOA1 loop conferring risk disease also blocks nanodomain both vivo human-induced dopaminergic neurons. Thus, we reveal mechanism neurons use connect critical survival.

Language: Английский

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Identification of secretory autophagy as a mechanism modulating activity-induced synaptic remodeling

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(16)

Published: April 8, 2024

The ability of neurons to rapidly remodel their synaptic structure and strength in response neuronal activity is highly conserved across species crucial for complex brain functions. However, mechanisms required elicit coordinate the acute, activity-dependent structural changes synapses are not well understood, as neurodevelopment plasticity tightly linked. Here, using an RNAi screen Drosophila against genes affecting nervous system functions humans, we uncouple cellular processes important synapse development. We find mutations associated with neurodegenerative mental health disorders 2-times more likely affect activity-induced remodeling than report that while both development at fly NMJ require macroautophagy (hereafter referred autophagy), bifurcation autophagy pathway differentially impacts plasticity. demonstrate enhances activation but diminishes degradative autophagy, thereby driving towards autophagy-based secretion. Presynaptic knockdown Snap29, Sec22, or Rab8, proteins implicated secretory pathway, sufficient abolish remodeling. This study uncovers a transsynaptic signaling mechanism modulating

Language: Английский

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Biological Basis of Cell Trafficking: A General Overview

Journal of Inherited Metabolic Disease, Journal Year: 2025, Volume and Issue: 48(1)

Published: Jan. 1, 2025

Cell trafficking is a tightly regulated biological process for the exchange of signals and metabolites between cell compartments, including four main processes: membrane (transport membrane-bound vesicles), autophagy, transport along cytoskeleton, contact sites. These processes are cross-sectional to cellular functions, ranging from transportation proteins, membranes, organelles elimination damaged proteins organelles. In consequence, crucial survival homeostasis, serving as cornerstone communication facilitating interactions both with surrounding environment different Disorders clinically pathophysiological diverse complex form largest group in recent International Classification Inherited Metabolic (ICIMD). this review, we explore categories principles that drive these processes. Instead delving profoundly into each pathway, comprehensive reviews on those topics already exist, offer broad overview molecular mechanisms behind trafficking, providing foundational understanding ease their entry subject enhance comprehension other articles featured Special Issue.

Language: Английский

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Stress dynamically modulates neuronal autophagy to gate depression onset

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders1. As a key modulator of homeostasis2, it remains elusive whether and how autophagy is engaged dynamics. Here we discover that acute activates, whereas chronic suppresses, mainly the lateral habenula (LHb). Systemic administration distinct antidepressant drugs similarly restores function LHb, suggesting LHb as common target. Genetic ablation neuronal promotes susceptibility, enhancing exerts rapid antidepressant-like effects. controls excitability, synaptic transmission plasticity by means on-demand degradation glutamate receptors. Collectively, this study shows causal role maintaining emotional homeostasis against stress. Disrupted implicated maladaptation stress, its reversal enhancers provides new strategy.

Language: Английский

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Synaptogenesis: unmasking molecular mechanisms using Caenorhabditis elegans

Genetics, Journal Year: 2023, Volume and Issue: 223(2)

Published: Jan. 11, 2023

Abstract The nematode Caenorhabditis elegans is a research model organism particularly suited to the mechanistic understanding of synapse genesis in nervous system. Armed with powerful genetics, knowledge complete connectomics, and modern genomics, studies using C. have unveiled multiple key regulators formation functional synapse. Importantly, many signaling networks display remarkable conservation throughout animals, underscoring contributions advance our brain. In this chapter, we will review up-to-date information contribution chemical synapses, from structure molecules synaptic remodeling.

Language: Английский

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Mutations in Parkinsonism-linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Feb. 15, 2023

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, have been implicated atypical Parkinsonism. SJ1 knock-in (SJ1-KI RQ ) mice carrying disease-linked mutation display neurological manifestations reminiscent of Here we report that auxilin knockout (Aux-KO) dystrophic changes subset nigrostriatal DAergic terminals similar those SJ1-KI mice. Furthermore, Aux-KO/SJ1-KI double mutant shorter lifespan more severe synaptic defects than single These include increase striatal nerve positive for markers PD risk protein SV2C, as well adaptive interneurons. The synergistic effect mutations demonstrates special lability neurons clathrin uncoating, with implications pathogenesis at least some forms this condition.

Language: Английский

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