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Cells
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Autophagy in the Nervous System
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Autophagy in the Nervous System

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 15812

Special Issue Editor

Prof. Dr. Jianhua Zhang

E-Mail Website
Guest Editor
Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
Interests: cellular and molecular mechanisms responsible for autophagy, cellular bioenergetics, oxidative stress and cell death, in the context of human diseases

Special Issue Information

Dear colleagues,

Autophagy is an essential component for cell function and survival. In post-mitotic neurons, autophagy is of particular importance in deterring the accumulation of toxic protein species and clearing existing toxic protein species, as well as dysfunctional cellular organelles. In astrocytes and glia, autophagy may also be important for the clearance of toxic materials and for modulating neuroinflammation. Dysfunction or insufficiency of autophagy is proposed to contribute to aging phenotypes, synaptic dysfunction, and to the development and progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This Special Issue will feature both original research articles and review articles that are relevant to autophagy in the nervous system.

Prof. Dr. Jianhua Zhang
Guest Editor

Manuscript Submission Information

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Keywords

  • autophagy
  • nervous system
  • neurons
  • cellular organelles

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Published Papers (4 papers)

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Research

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25 pages, 7001 KiB  
Article
Potent New Targets for Autophagy Enhancement to Delay Neuronal Ageing
by Janka Szinyákovics, Fanni Keresztes, Eszter Anna Kiss, Gergő Falcsik, Tibor Vellai and Tibor Kovács
Cells 2023, 12(13), 1753; https://doi.org/10.3390/cells12131753 - 30 Jun 2023
Cited by 3 | Viewed by 2819
Abstract
Autophagy is a lysosomal-dependent degradation process of eukaryotic cells responsible for breaking down unnecessary and damaged intracellular components. Autophagic activity gradually declines with age due to genetic control, and this change contributes to the accumulation of cellular damage at advanced ages, thereby causing [...] Read more.
Autophagy is a lysosomal-dependent degradation process of eukaryotic cells responsible for breaking down unnecessary and damaged intracellular components. Autophagic activity gradually declines with age due to genetic control, and this change contributes to the accumulation of cellular damage at advanced ages, thereby causing cells to lose their functionality and viability. This could be particularly problematic in post-mitotic cells including neurons, the mass destruction of which leads to various neurodegenerative diseases. Here, we aim to uncover new regulatory points where autophagy could be specifically activated and test these potential drug targets in neurodegenerative disease models of Drosophila melanogaster. One possible way to activate autophagy is by enhancing autophagosome–lysosome fusion that creates the autolysosome in which the enzymatic degradation happens. The HOPS (homotypic fusion and protein sorting) and SNARE (Snap receptor) protein complexes regulate the fusion process. The HOPS complex forms a bridge between the lysosome and autophagosome with the assistance of small GTPase proteins. Thus, small GTPases are essential for autolysosome maturation, and among these proteins, Rab2 (Ras-associated binding 2), Rab7, and Arl8 (Arf-like 8) are required to degrade the autophagic cargo. For our experiments, we used Drosophila melanogaster as a model organism. Nerve-specific small GTPases were silenced and overexpressed. We examined the effects of these genetic interventions on lifespan, climbing ability, and autophagy. Finally, we also studied the activation of small GTPases in a Parkinson’s disease model. Our results revealed that GTP-locked, constitutively active Rab2 (Rab2-CA) and Arl8 (Arl8-CA) expression reduces the levels of the autophagic substrate p62/Ref(2)P in neurons, extends lifespan, and improves the climbing ability of animals during ageing. However, Rab7-CA expression dramatically shortens lifespan and inhibits autophagy. Rab2-CA expression also increases lifespan in a Parkinson’s disease model fly strain overexpressing human mutant (A53T) α-synuclein protein. Data provided by this study suggests that Rab2 and Arl8 serve as potential targets for autophagy enhancement in the Drosophila nervous system. In the future, it might be interesting to assess the effect of Rab2 and Arl8 coactivation on autophagy, and it would also be worthwhile to validate these findings in a mammalian model and human cell lines. Molecules that specifically inhibit Rab2 or Arl8 serve as potent drug candidates to modulate the activity of the autophagic process in treating neurodegenerative pathologies. In the future, it would be reasonable to investigate which GAP enzyme can inhibit Rab2 or Arl8 specifically, but not affect Rab7, with similar medical purposes. Full article
(This article belongs to the Special Issue Autophagy in the Nervous System)
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16 pages, 2342 KiB  
Article
Autophagy Function and Benefits of Autophagy Induction in Models of Spinocerebellar Ataxia Type 3
by Maxinne Watchon, Luan Luu, Stuart K. Plenderleith, Kristy C. Yuan and Angela S. Laird
Cells 2023, 12(6), 893; https://doi.org/10.3390/cells12060893 - 14 Mar 2023
Cited by 6 | Viewed by 2310
Abstract
Background: Spinocerebellar ataxia 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. The presence of this genetic expansion results in an ataxin-3 protein containing a polyglutamine [...] Read more.
Background: Spinocerebellar ataxia 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. The presence of this genetic expansion results in an ataxin-3 protein containing a polyglutamine repeat region, which renders the ataxin-3 protein aggregation prone. Formation of ataxin-3 protein aggregates is linked with neuronal loss and, therefore, the development of motor deficits. Methods: Here, we investigated whether the autophagy protein quality control pathway, which is important in the process of protein aggregate removal, is impaired in a cell culture and zebrafish model of SCA3. Results: We found that SH-SY5Y cells expressing human ataxin-3 containing polyglutamine expansion exhibited aberrant levels of autophagy substrates, including increased p62 and decreased LC3II (following bafilomycin treatment), compared to the controls. Similarly, transgenic SCA3 zebrafish showed signs of autophagy impairment at early disease stages (larval), as well as p62 accumulation at advanced age stages (18 months old). We then examined whether treating with compounds known to induce autophagy activity, would aid removal of human ataxin-3 84Q and improve the swimming of the SCA3 zebrafish larvae. We found that treatment with loperamide, trehalose, rapamycin, and MG132 each improved the swimming of the SCA3 zebrafish compared to the vehicle-treated controls. Conclusion: We propose that signs of autophagy impairment occur in the SH-SY5Y model of SCA3 and SCA3 zebrafish at larval and advanced age stages. Treatment of the larval SCA3 zebrafish with various compounds with autophagy induction capacity was able to produce the improved swimming of the zebrafish, suggesting the potential benefit of autophagy-inducing compounds for the treatment of SCA3. Full article
(This article belongs to the Special Issue Autophagy in the Nervous System)
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15 pages, 2955 KiB  
Article
Cytosolic HMGB1 Mediates LPS-Induced Autophagy in Microglia by Interacting with NOD2 and Suppresses Its Proinflammatory Function
by Seung-Woo Kim, Sang-A Oh, Song-I Seol, Dashdulam Davaanyam and Ja-Kyeong Lee
Cells 2022, 11(15), 2410; https://doi.org/10.3390/cells11152410 - 4 Aug 2022
Cited by 12 | Viewed by 3484
Abstract
The high mobility group box 1 (HMGB1), a well-known danger-associated molecule pattern (DAMP) molecule, is a non-histone chromosomal protein localized in the nucleus under normal physiological conditions. HMGB1 exhibits diverse functions depending on its subcellular location. In the present study, we investigated the [...] Read more.
The high mobility group box 1 (HMGB1), a well-known danger-associated molecule pattern (DAMP) molecule, is a non-histone chromosomal protein localized in the nucleus under normal physiological conditions. HMGB1 exhibits diverse functions depending on its subcellular location. In the present study, we investigated the role of HMGB1-induced autophagy in the lipopolysaccharide (LPS)-treated BV2 microglial cell line in mediating the transition between the inflammatory and autophagic function of the nucleotide-binding oligomerization domain-containing 2 (NOD2), a cytoplasmic pattern-recognition receptor. The induction of the microtubule-associated protein 1 light chain 3 (LC3), an autophagy biomarker, was detected slowly in BV2 cells after the LPS treatment, and peak induction was detected at 12 h. Under these conditions, NOD2 level was significantly increased and the binding between HMGB1 and NOD2 and between HMGB1 and ATG16L1 was markedly enhanced and the temporal profiles of the LC3II induction and HMGB1-NOD2 and HMGB1-ATG16L1 complex formation coincided with the cytosolic accumulation of HMGB1. The LPS-mediated autophagy induction was significantly suppressed in BV2 cells after HMGB1 or NOD2 knock-down (KD), indicating that HMGB1 contributes to NOD2-mediated autophagy induction in microglia. Moreover, NOD2-RIP2 interaction-mediated pro-inflammatory cytokine induction and NF-κB activity were significantly enhanced in BV2 cells after HMGB1 KD, indicating that HMGB1 plays a critical role in the modulation of NOD2 function between pro-inflammation and pro-autophagy in microglia. The effects of the cell-autonomous pro-autophagic pathway operated by cytoplasmic HMGB1 may be beneficial, whereas those from the paracrine pro-inflammatory pathway executed by extracellularly secreted HMGB1 can be detrimental. Thus, the overall functional significance of HMGB1-induced autophagy is different, depending on its temporal activity. Full article
(This article belongs to the Special Issue Autophagy in the Nervous System)
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Review

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34 pages, 3455 KiB  
Review
Molecular Mechanism and Regulation of Autophagy and Its Potential Role in Epilepsy
by Hanxiao Zhu, Wei Wang and Yun Li
Cells 2022, 11(17), 2621; https://doi.org/10.3390/cells11172621 - 23 Aug 2022
Cited by 22 | Viewed by 6259
Abstract
Autophagy is an evolutionally conserved degradation mechanism for maintaining cell homeostasis whereby cytoplasmic components are wrapped in autophagosomes and subsequently delivered to lysosomes for degradation. This process requires the concerted actions of multiple autophagy-related proteins and accessory regulators. In neurons, autophagy is dynamically [...] Read more.
Autophagy is an evolutionally conserved degradation mechanism for maintaining cell homeostasis whereby cytoplasmic components are wrapped in autophagosomes and subsequently delivered to lysosomes for degradation. This process requires the concerted actions of multiple autophagy-related proteins and accessory regulators. In neurons, autophagy is dynamically regulated in different compartments including soma, axons, and dendrites. It determines the turnover of selected materials in a spatiotemporal control manner, which facilitates the formation of specialized neuronal functions. It is not surprising, therefore, that dysfunctional autophagy occurs in epilepsy, mainly caused by an imbalance between excitation and inhibition in the brain. In recent years, much attention has been focused on how autophagy may cause the development of epilepsy. In this article, we overview the historical landmarks and distinct types of autophagy, recent progress in the core machinery and regulation of autophagy, and biological roles of autophagy in homeostatic maintenance of neuronal structures and functions, with a particular focus on synaptic plasticity. We also discuss the relevance of autophagy mechanisms to the pathophysiology of epileptogenesis. Full article
(This article belongs to the Special Issue Autophagy in the Nervous System)
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