Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9

Neuron, Journal Year: 2022, Volume and Issue: 110(5), P. 824 - 840.e10

Published: Jan. 21, 2022

Autophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, locally regulated, increases in response to activity. The mechanisms that couple autophagosome synaptic activity remain unknown. In this study, we determine trafficking of ATG-9, the only transmembrane protein core autophagy pathway, links vesicle cycle with autophagy. ATG-9-positive vesicles C. elegans are generated from trans-Golgi network via AP-3-dependent budding delivered presynaptic sites. At sites, ATG-9 undergoes exo-endocytosis an activity-dependent manner. Mutations disrupt endocytosis, including lesion synaptojanin 1 associated Parkinson's disease, result abnormal accumulation clathrin-rich foci defects activity-induced Our findings uncover regulated key steps sites provide evidence couples cycle.

Language: Английский

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Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons

Cell Reports, Journal Year: 2021, Volume and Issue: 35(4), P. 109034 - 109034

Published: April 1, 2021

Lysosomal trafficking and maturation in neurons remain poorly understood are unstudied vivo despite high disease relevance. We generated neuron-specific transgenic mice to track vesicular CTSD acquisition, acidification, traffic within the autophagic-lysosomal pathway vivo, revealing that mature lysosomes restricted from axons. Moreover, TGN-derived transport carriers (TCs), not lysosomes, supply lysosomal components axonal organelles. Ultrastructurally distinctive TCs containing TGN markers enter axons, engaging autophagic vacuoles late endosomes. This process is markedly upregulated dystrophic axons of Alzheimer models. In cultured neurons, most LAMP1 vesicles weakly acidic shuttle bidirectionally, conferring limited degradative capability retrograde organelles before they fully perikarya. The minor subpopulation attaining robust acidification Rab7+ endosomes/amphisomes, lysosomes. Restricted lysosome entry into explains unique distribution their vulnerability toward neuritic dystrophy disease.

Language: Английский

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Lysosomal Stress Response (LSR): Physiological Importance and Pathological Relevance

Journal of Neuroimmune Pharmacology, Journal Year: 2021, Volume and Issue: 16(2), P. 219 - 237

Published: March 22, 2021

Language: Английский

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Role of Ceramides and Sphingolipids in Parkinson's Disease

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(12), P. 168000 - 168000

Published: Feb. 9, 2023

Sphingolipids, including the basic ceramide, are a subset of bioactive lipids that consist many different species. Sphingolipids indispensable for proper neuronal function, and an increasing number studies have emerged on complexity importance these in (almost) all biological processes. These include regulation mitochondrial autophagy, endosomal trafficking, which affected Parkinson's disease (PD). PD is second most common neurodegenerative disorder characterized by loss dopaminergic neurons. Currently, cannot be cured due to lack knowledge exact pathogenesis. Nonetheless, important advances identified molecular changes function. Furthermore, recent ceramide alterations patients suffering from PD, models, suggesting critical interaction between sphingolipids related cellular processes PD. For instance, autosomal recessive forms cause dysfunction, energy production or clearance, directly influenced manipulating sphingolipids. Additionally, endo-lysosomal recycling genes dominant disease, such as VPS35 SNCA. crucial transporting compartments where they will execute their functions. This review discuss defects abnormal activity role play vital

Language: Английский

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Role of microglia autophagy and mitophagy in age-related neurodegenerative diseases

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 14

Published: April 26, 2023

Microglia, characterized by responding to damage, regulating the secretion of soluble inflammatory mediators, and engulfing specific segments in central nervous system (CNS), function as key immune cells CNS. Emerging evidence suggests that microglia coordinate responses CNS play a pivotal role pathogenesis age-related neurodegenerative diseases (NDDs). Remarkably, autophagy participates regulation subcellular substances, which includes degradation misfolded proteins other harmful constituents produced neurons. Therefore, regulates neuronal homeostasis maintenance process neuroinflammation. In this review, we aimed at highlighting NDDs. Besides mechanistic co-interaction between different kinds NDDs, also emphasized potential therapeutic agents approaches could be utilized onset progression these through modulating autophagy, including promising nanomedicines. Our review provides valuable reference for subsequent studies focusing on treatments disorders. The exploration development nanomedicines greatly enhances current understanding

Language: Английский

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Synaptic Vesicle Recycling and the Endolysosomal System: A Reappraisal of Form and Function

Frontiers in Synaptic Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Feb. 25, 2022

The endolysosomal system is present in all cell types. Within these cells, it performs a series of essential roles, such as trafficking and sorting membrane cargo, intracellular signaling, control metabolism degradation. A specific compartment within central neurons, called the presynapse, mediates inter-neuronal communication via fusion neurotransmitter-containing synaptic vesicles (SVs). localized recycling SVs their organization into functional pools widely assumed to be discrete mechanism, that only intersects with at points. However, evidence emerging molecules for function also have key roles SV life cycle, suggesting they form continuum rather than being isolated processes. In this review, we summarize propose an alternative model presynapse. This includes hypotheses intermediates represent pools, cargo mediated manipulation process can result both plastic changes neurotransmitter release pathophysiology neurodegeneration.

Language: Английский

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Neuronal endolysosomal acidification relies on interactions between transmembrane protein 184B (TMEM184B) and the vesicular proton pump

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Abstract Disruption of endolysosomal acidification is a hallmark several neurodevelopmental and neurodegenerative disorders. Impaired causes accumulation toxic protein aggregates disrupts neuronal homeostasis, yet the molecular mechanisms regulating pH in neurons remain poorly understood. A critical regulator lumenal vacuolar ATPase (V-ATPase), proton pump whose activity depends on dynamic assembly its V0 V1 subdomains. In this study, we identify transmembrane 184B (TMEM184B) as novel neurons. TMEM184B an evolutionarily conserved 7-pass required for synaptic structure function, sequence variation disorders, but mechanism effect unknown. We performed proteomic analysis TMEM184B-interacting proteins identified enrichment components involved endosomal trafficking including V-ATPase. localizes to early late endosomes, further supporting role system. Loss results significant reductions within cultured mouse cortical This alteration associated with impaired V-ATPase subcomplexes mutant brain, suggesting by which promotes flux through pathway. Overall, these findings new contributor maintaining function provide mechanistic basis disrupted human TMEM184B-associated nervous system Significance Statement Endolysosomal essential regulation remains Here, key process, establishing first known cellular role. show that interacts (V-ATPase) subdomains, facilitating acidification. neurons, potentially impairing proteostasis. These reveal maintenance insight into link neurological work advances our understanding suggests could improve outcomes diseases involving lysosomal dysfunction.

Language: Английский

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The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

Cells, Journal Year: 2021, Volume and Issue: 10(3), P. 579 - 579

Published: March 6, 2021

Parkinson’s disease (PD) is a complex neurodegenerative disorder that currently incurable. As consequence of an incomplete understanding the etiology disease, therapeutic strategies mainly focus on symptomatic treatment. Even though majority PD cases remain idiopathic (~90%), several genes have been identified to be causative for PD, facilitating generation animal models are good alternative study pathways and increase our underlying mechanisms PD. Drosophila melanogaster has proven excellent model in these studies. In this review, we will discuss different flies key findings affected Several molecular changes identified, which mitochondrial dysfunction defective endo-lysosomal pathway emerge most relevant pathogenesis. Studies significantly contributed knowledge how affect interact enabling better providing possible targets treatment some already resulted clinical trials.

Language: Английский

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Dying by fire: noncanonical functions of autophagy proteins in neuroinflammation and neurodegeneration

Neural Regeneration Research, Journal Year: 2021, Volume and Issue: 17(2), P. 246 - 246

Published: July 10, 2021

Neuroinflammation and neurodegeneration are key components in the establishment progression of neurodegenerative diseases including Alzheimer's Disease (AD). Over past decade increasing evidence is emerging for use canonical autophagy machinery pathways that characterized by LC3 lipidation yet distinct from traditional macro-autophagy. One such pathway utilizes to target endosomes, a process termed LC3-associated endocytosis (LANDO), has recently been identified regulates neuroinflammation. Abrogation LANDO microglia cells results propensity elevated neuroinflammatory cytokine production. Using well-established 5xFAD model AD interrogate regulation, impairment through deletion upstream regulator Rubicon or other downstream components, exacerbated disease onset severity, while microglial alone had no measurable effect. Mice presented with robust deposition neurotoxic protein β-amyloid (Aβ), activation inflammatory production, tau phosphorylation, aggressive culminating severe memory impairment. LANDO-deficiency impaired recycling receptors recognize Aβ, TLR4 TREM2. WD-domain ATG16L, revealed role spontaneous age-associated AD. LANDO-deficient mice aged 2 years advanced AD-like pathology correlative observed human patients. Together, these studies illustrate an important regulating CNS immune protection against neurodegeneration. New demonstrates putative linkage between as cell death regulation via apoptosis possibly necroptosis. Herein, we provide review non-canonical mechanisms alter could have significant impact furthering our understanding not only like AD, but likely beyond.

Language: Английский

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Organization of Presynaptic Autophagy-Related Processes

Frontiers in Synaptic Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: March 17, 2022

Brain synapses pose special challenges on the quality control of their protein machineries as they are far away from neuronal soma, display a high potential for plastic adaptation and have energy demand to fulfill physiological tasks. This applies in particular presynaptic part where neurotransmitter is released synaptic vesicles, which turn be recycled refilled complex membrane trafficking cycle. Pathways remove outdated damaged proteins include ubiquitin-proteasome system acting cytoplasm well membrane-associated endolysosomal autophagy systems. Here we focus latter systems review what known about spatial organization endolysomal processes within presynapse. We provide an inventory components these degradative were found present boutons might anchored apparatus. identify three structures reported interact with constituents membrane-based protein-degradation pathways therefore may serve docking stations. These (i) scaffolding cytomatrix at active zone, such Bassoon or Clarinet, (ii) endocytic machinery localized mainly peri-active (iii) vesicles. Finally, sketch scenarios, how autophagic cargos tagged recruited cellular mechanisms govern turnover

Language: Английский

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