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

Neuron, Год журнала: 2023, Номер 111(9), С. 1402 - 1422.e13

Опубликована: Фев. 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.

Язык: Английский

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Biological Basis of Cell Trafficking: A General Overview

Journal of Inherited Metabolic Disease, Год журнала: 2025, Номер 48(1)

Опубликована: Янв. 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.

Язык: Английский

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Spermidine Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders

Journal of Inherited Metabolic Disease, Год журнала: 2025, Номер 48(1)

Опубликована: Янв. 1, 2025

Язык: Английский

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Molecular Mechanism and Regulation of Autophagy and Its Potential Role in Epilepsy

Cells, Год журнала: 2022, Номер 11(17), С. 2621 - 2621

Опубликована: Авг. 23, 2022

Autophagy is an evolutionally conserved degradation mechanism for maintaining cell homeostasis whereby cytoplasmic components are wrapped in autophagosomes and subsequently delivered to lysosomes degradation. This process requires the concerted actions of multiple autophagy-related proteins accessory regulators. In neurons, autophagy dynamically regulated different compartments including soma, axons, dendrites. It determines turnover selected materials a spatiotemporal control manner, which facilitates formation specialized neuronal functions. not surprising, therefore, that dysfunctional occurs epilepsy, mainly caused by imbalance between excitation inhibition brain. recent years, much attention has been focused on how may cause development epilepsy. this article, we overview historical landmarks distinct types autophagy, progress core machinery regulation biological roles homeostatic maintenance structures functions, with particular focus synaptic plasticity. We also discuss relevance mechanisms pathophysiology epileptogenesis.

Язык: Английский

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The Role of Rab Proteins in Parkinson’s Disease Synaptopathy

Biomedicines, Год журнала: 2022, Номер 10(8), С. 1941 - 1941

Опубликована: Авг. 10, 2022

In patients affected by Parkinson's disease (PD), the most common neurodegenerative movement disorder, brain is characterized loss of dopaminergic neurons in nigrostriatal system, leading to dyshomeostasis basal ganglia network activity that linked motility dysfunction. PD mostly arises as an age-associated sporadic disease, but several genetic forms also exist. Compelling evidence supports synaptic damage and dysfunction characterize very early phases either or this synaptopathy drives retrograde terminal-to-cell body degeneration, culminating neuronal loss. The Ras-associated binding protein (Rab) family small GTPases, which involved maintenance vesicular trafficking, architecture function central nervous has recently emerged among major players synaptopathy. manuscript, we provide overview main findings supporting involvement Rabs pathophysiology, highlight how Rab alterations participate onset

Язык: Английский

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Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 4, 2024

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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PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth

Cell Reports, Год журнала: 2025, Номер 44(4), С. 115483 - 115483

Опубликована: Апрель 1, 2025

Highlights•In neurons, PDZD8 primarily localizes to ER-late endosome/lysosome membrane contact sites•PDZD8 is required for activity-dependent synaptic growth•PDZD8 promotes bouton formation through an autophagy-dependent mechanism•PDZD8 lysosome maturation and turnover increase autophagic fluxSummaryBuilding connections requires coordinating a host of cellular activities from cell signaling protein turnover, placing high demand on intracellular communication. Membrane sites (MCSs) formed between organelles have emerged as key hubs diverse activities, yet their roles in the developing nervous system remain obscure. We investigate vivo function endoplasmic reticulum (ER) MCS tethering lipid-transfer PDZD8, which was recently linked intellectual disability, system. find that multiple paradigms. sufficient drive excess mechanism synapse development when autophagy limited. accelerates flux by promoting at MCSs. propose functions during periods demand, including growth.Graphical abstract

Язык: Английский

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Neuronal autophagy controls excitability via ryanodine receptor–mediated regulation of calcium-activated potassium channel function

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(17)

Опубликована: Апрель 23, 2025

Glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures and promoting epileptogenesis. Recent data suggest that altered autophagy can contribute to the occurrence of epilepsy. We examined physiology by generating knockout mice conditionally lacking essential protein ATG5 glutamatergic neurons. demonstrate conditional genetic blockade results action potential narrowing, axonal hyperexcitability, an increase kainate-induced epileptiform bursts ex vivo, indicative lower threshold for induction epileptic seizures. Neuronal hyperexcitability hippocampal slices from is due elevated activity large conductance calcium-activated potassium channel BKCa downstream calcium influx via endoplasmic reticulum (ER)-localized ryanodine receptor (RYR). Consistently, pharmacological RYR or function rescued reduced frequency cKO brain slices. Our findings reveal physiological regulation excitability control RYR-mediated release, thereby, mammalian brain.

Язык: Английский

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Epilepsy and autophagy modulators: a therapeutic split

Autophagy, Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

Epilepsy is a neurological disease characterized by repeated unprovoked seizure. controlled anti-epileptic drugs (AEDs); however, one third of epileptic patients have symptoms that are not AEDs in condition called refractory epilepsy. Dysregulation macroautophagy/autophagy involved the pathogenesis Autophagy prevents development and progression epilepsy through regulating balance between inhibitory excitatory neurotransmitters. Induction autophagy autophagy-related proteins could be novel therapeutic strategy management Despite protective role against epileptogenesis epilepsy, its status epilepticus perplexing might reflect nature as double-edged sword. inducers play critical reducing seizure frequency severity, an adjuvant treatment However, inhibitors also anticonvulsant effect. Therefore, aim present mini-review to discuss potential how modulators affect

Язык: Английский

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