Neuronal Autophagy: Regulations and Implications in Health and Disease

Cells, Год журнала: 2024, Номер 13(1), С. 103 - 103

Опубликована: Янв. 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.

Язык: Английский

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Emerging roles of ATG9/ATG9A in autophagy: implications for cell and neurobiology

Autophagy, Год журнала: 2024, Номер 20(11), С. 2373 - 2387

Опубликована: Авг. 4, 2024

Atg9, the only transmembrane protein among many autophagy-related proteins, was first identified in year 2000 yeast. Two homologs of ATG9A and ATG9B, have been found mammals. While ATG9B shows a tissue-specific expression pattern, such as placenta pituitary gland, is ubiquitously expressed. Additionally, deficiency leads to severe defects not at molecular cellular levels but also organismal level, suggesting key fundamental roles for ATG9A. The subcellular localization on small vesicles its functional relevance autophagy suggested potential role lipid supply during autophagosome biogenesis. Nevertheless, precise autophagic process has remained long-standing mystery, especially neurons. Recent findings, however, including structural, proteomic, biochemical analyses, provided new insights into function expansion phagophore membrane. In this review, we aim understand various aspects ATG9 (in invertebrates plants)/ATG9A mammals), localization, trafficking, other functions, nonneuronal cells neurons by comparing recent discoveries related ATG9/ATG9A proposing directions future research.

Язык: Английский

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Presynaptic Autophagy and the Connection With Neurotransmission

Frontiers in Cell and Developmental Biology, Год журнала: 2021, Номер 9

Опубликована: Дек. 17, 2021

Autophagy is an evolutionary conserved catabolic pathway essential for the maintenance of cellular homeostasis. Defective proteins and organelles are engulfed by autophagosomal membranes which fuse with lysosomes cargo degradation. In neurons, orchestrated progression autophagosome formation maturation occurs in distinct subcellular compartments. For synapses, distance from soma oxidative stress generated during intense neuronal activity pose a challenge to maintain protein constitutes crucial mechanism proper functioning this unique vulnerable compartment. We now beginning understand how autophagy regulated at pre-synaptic terminals pathway, when imbalanced, impacts on synaptic function -ultimately- survival. review here current state art “synaptic autophagy”, emphasis biogenesis autophagosomes provide overview existing knowledge signals inducing highlight interplay between neurotransmission, perspectives future research.

Язык: Английский

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Neuronal autophagy in the control of synapse function

Neuron, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Neurons are long-lived postmitotic cells that capitalize on autophagy to remove toxic or defective proteins and organelles maintain neurotransmission the integrity of their functional proteome. Mutations in genes cause congenital diseases, sharing prominent brain dysfunctions including epilepsy, intellectual disability, neurodegeneration. Ablation core neurons glia disrupts normal behavior, leading motor deficits, memory impairment, altered sociability, which associated with defects synapse maturation, plasticity, neurotransmitter release. In spite importance for physiology, substrates neuronal mechanisms by affect synaptic function health disease remain controversial. Here, we summarize current state knowledge autophagy, address existing controversies inconsistencies field, provide a roadmap future research role control function.

Язык: Английский

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Conserved components of the macroautophagy machinery in Caenorhabditis elegans

Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 4, 2025

Abstract Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation recycling. In Caenorhabditis elegans, autophagy participates diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, adaptive immunity. Genetic screens C. elegans have identified set metazoan-specific genes that form basis our molecular understanding steps unique pathway multicellular organisms. Suppressor uncovered multiple mechanisms modulate activity under physiological conditions. also provides model investigate how is coordinately controlled at an organismal level. this chapter, we will discuss machinery, regulation, functions autophagy, methods utilized monitoring during development.

Язык: Английский

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Macroautophagy at the service of synapses

Current Opinion in Neurobiology, Год журнала: 2025, Номер 93, С. 103054 - 103054

Опубликована: Май 24, 2025

Post-mitotic and highly polarized neurons are dependent on the fitness of their synapses, which often found a long distance away from soma. How synaptic proteome is maintained, dynamically reshaped, continuously turned over topic intense investigation. Autophagy, conserved, lysosome-mediated degradation pathway has emerged as vital component long-term neuronal maintenance, now more specifically homeostasis. Here, we review most recent findings how autophagy undergoes both dynamic local regulation at synapse, it contributes to pre- post-synaptic proteostasis function. We also discuss insights open questions that this new evidence brings.

Язык: Английский

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Organization of Presynaptic Autophagy-Related Processes

Frontiers in Synaptic Neuroscience, Год журнала: 2022, Номер 14

Опубликована: Март 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

Язык: Английский

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ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons

Acta Physiologica, Год журнала: 2024, Номер 240(8)

Опубликована: Июнь 5, 2024

Abstract Aim Understanding the physiological role of ATP6V1A, a component cytosolic V 1 domain proton pump vacuolar ATPase, in regulating neuronal development and function. Methods Modeling loss function Atp6v1a primary murine hippocampal neurons studying morphology by immunoimaging, electrophysiological recordings electron microscopy. Results depletion affects neurite elongation, stabilization, excitatory synapses prevents synaptic rearrangement upon induction plasticity. These phenotypes are due to an overall decreased expression subunits, that leads impairment lysosomal pH‐regulation autophagy progression with accumulation aberrant lysosomes at soma enlarged vacuoles boutons. Conclusions data suggest ATP6V1A surveillance integrity plasticity highlight pathophysiological significance alteration is associated neurodevelopmental neurodegenerative diseases. The further support pivotal involvement flux maintaining proper connectivity adaptive properties.

Язык: Английский

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Apache is a neuronal player in autophagy required for retrograde axonal transport of autophagosomes

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Окт. 5, 2024

Abstract Neurons are dependent on efficient quality control mechanisms to maintain cellular homeostasis and function due their polarization long-life span. Autophagy is a lysosomal degradative pathway that provides nutrients during starvation recycles damaged and/or aged proteins organelles. In neurons, autophagosomes constitutively form in distal axons at synapses trafficked retrogradely the cell soma fuse with lysosomes for cargo degradation. How neuronal autophagy organized controlled remains poorly understood. Several presynaptic endocytic have been shown regulate both synaptic vesicle recycling autophagy. Here, by combining electron, fluorescence, live imaging microscopy biochemical analysis, we show neuron-specific protein APache, AP-2 interactor, functions neurons as an important player process, regulating retrograde transport of autophagosomes. We found APache colocalizes co-traffics primary cortical induction mTOR inhibition increases LC3 levels boutons. silencing causes blockade autophagic flux preventing clearance p62/SQSTM1, leading severe accumulation amphisomes terminals along neurites defective TrkB-containing signaling axons. Together, our data identify regulator cycle, potentially cooperation AP-2, hypothesize its dysfunctions contribute early impairments neurodegenerative conditions associated impaired

Язык: Английский

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Turning garbage into gold: Autophagy in synaptic function

Current Opinion in Neurobiology, Год журнала: 2024, Номер 90, С. 102937 - 102937

Опубликована: Дек. 12, 2024

Язык: Английский

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