Special Issue "Autophagy in Neurodegenerative Diseases"

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

Deadline for manuscript submissions: closed (30 September 2019).

Special Issue Editor

Dr. Marta Martinez-Vicente
E-Mail Website1 Website2
Guest Editor
Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute-CIBERNED, Barcelona, Spain
Interests: autophagy; neurodegeneration; lysosome; Parkinson’s disease; Huntington’s disease; synuclein

Special Issue Information

Dear Colleagues,

Cellular homeostasis depends on the proper functioning of quality control systems, among which autophagy plays a pivotal role. The clearance of misfolded proteins and aggregates and the turnover of organelles are essential to guarantee normal cellular function, particularly in post-mitotic cells like neurons, which require effective and constitutive autophagic activity to maintain cellular viability.

Growing evidence indicates a role of autophagy dysfunction in many human diseases, especially in neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease Huntington’s disease and amyotrophic lateral sclerosis, among others. In recent years, a vast amount of work has facilitated a better understanding of the role of autophagy in neurons and the origin and consequences of autophagic failure in each neurodegenerative disease.

The elucidation of dysfunctional autophagic processes may help in the design of new therapeutic approaches based on autophagy modulation to ultimately attenuate or prevent neurodegeneration. 

This Special Issue aims to summarize the current knowledge on the role of autophagy in neurodegeneration and the ongoing therapeutic modulation of autophagy as a new challenge to fight neurodegenerative diseases.

Dr. Marta Martinez-Vicente
Guest Editor

Manuscript Submission Information

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Keywords

  • autophagy
  • lysosomal dysfunction
  • neurodegenerative diseases
  • neurodegeneration
  • Parkinson’s disease,
  • Huntington’s disease
  • Alzheimer’s disease
  • mitophagy
  • endosomal–lysosomal system
  • therapeutic autophagy modulators

Published Papers (7 papers)

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Editorial

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Open AccessEditorial
Novel Therapeutic Approach to Induce Autophagy in a Drosophila Model for Huntington’s Disease
Cells 2020, 9(2), 495; https://doi.org/10.3390/cells9020495 - 21 Feb 2020
Abstract
Autophagy induction is an attractive therapeutic approach to ameliorate aggregate accumulation in many neurodegenerative diseases. In Huntington’s disease (HD) in vivo models, a number of genetic and pharmacological mechanisms aimed to induce autophagy have been successfully tested [1], demonstrating the role of autophagy [...] Read more.
Autophagy induction is an attractive therapeutic approach to ameliorate aggregate accumulation in many neurodegenerative diseases. In Huntington’s disease (HD) in vivo models, a number of genetic and pharmacological mechanisms aimed to induce autophagy have been successfully tested [1], demonstrating the role of autophagy in promoting the elimination of mutant huntingtin (mHTT) aggregates and its neuroprotective effect. In their recent report in Cells, Vernizzi and colleagues [2] presented a totally new mechanism to induce autophagy, promote the elimination of mHTT aggregates, and ultimately achieve neuroprotection. This novel therapy is based on the overexpression of glutamine synthetase 1 (GS1), an enzyme that catalyzes the synthesis of L-glutamine from L-glutamate as part of the glutamate glutamine cycle (GGC), a physiological process between glia and neurons that controls glutamate homeostasis [3].[...] Full article
(This article belongs to the Special Issue Autophagy in Neurodegenerative Diseases)

Research

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Open AccessArticle
Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington’s Disease
Cells 2020, 9(1), 196; https://doi.org/10.3390/cells9010196 - 13 Jan 2020
Abstract
Glutamine Synthetase 1 (GS1) is a key enzyme that catalyzes the ATP-dependent synthesis of l-glutamine from l-glutamate and is also member of the Glutamate Glutamine Cycle, a complex physiological process between glia and neurons that controls glutamate homeostasis and is often [...] Read more.
Glutamine Synthetase 1 (GS1) is a key enzyme that catalyzes the ATP-dependent synthesis of l-glutamine from l-glutamate and is also member of the Glutamate Glutamine Cycle, a complex physiological process between glia and neurons that controls glutamate homeostasis and is often found compromised in neurodegenerative diseases including Huntington’s disease (HD). Here we report that the expression of GS1 in neurons ameliorates the motility defects induced by the expression of the mutant Htt, using a Drosophila model for HD. This phenotype is associated with the ability of GS1 to favor the autophagy that we associate with the presence of reduced Htt toxic protein aggregates in neurons expressing mutant Htt. Expression of GS1 prevents the TOR activation and phosphorylation of S6K, a mechanism that we associate with the reduced levels of essential amino acids, particularly of arginine and asparagine important for TOR activation. This study reveals a novel function for GS1 to ameliorate neuronal survival by changing amino acids’ levels that induce a “starvation-like” condition responsible to induce autophagy. The identification of novel targets that inhibit TOR in neurons is of particular interest for the beneficial role that autophagy has in preserving physiological neuronal health and in the mechanisms that eliminate the formation of toxic aggregates in proteinopathies. Full article
(This article belongs to the Special Issue Autophagy in Neurodegenerative Diseases)
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Open AccessArticle
C9orf72 Proteins Regulate Autophagy and Undergo Autophagosomal or Proteasomal Degradation in a Cell Type-Dependent Manner
Cells 2019, 8(10), 1233; https://doi.org/10.3390/cells8101233 - 10 Oct 2019
Abstract
Dysfunctional autophagy or ubiquitin-proteasome system (UPS) are suggested to underlie abnormal protein aggregation in neurodegenerative diseases. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)-associated C9orf72 is implicated in autophagy, but whether it activates or inhibits autophagy is partially controversial. Here, we utilized knockdown [...] Read more.
Dysfunctional autophagy or ubiquitin-proteasome system (UPS) are suggested to underlie abnormal protein aggregation in neurodegenerative diseases. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)-associated C9orf72 is implicated in autophagy, but whether it activates or inhibits autophagy is partially controversial. Here, we utilized knockdown or overexpression of C9orf72 in mouse N2a neuroblastoma cells or cultured neurons to elucidate the potential role of C9orf72 proteins in autophagy and UPS. Induction of autophagy in C9orf72 knockdown N2a cells led to decreased LC3BI to LC3BII conversion, p62 degradation, and formation of LC3-containing autophagosomes, suggesting compromised autophagy. Proteasomal activity was slightly decreased. No changes in autophagy nor proteasomal activity in C9orf72-overexpressing N2a cells were observed. However, in these cells, autophagy induction by serum starvation or rapamycin led to significantly decreased C9orf72 levels. The decreased levels of C9orf72 in serum-starved N2a cells were restored by the proteasomal inhibitor lactacystin, but not by the autophagy inhibitor bafilomycin A1 (BafA1) treatment. These data suggest that C9orf72 undergoes proteasomal degradation in N2a cells during autophagy. Lactacystin significantly elevated C9orf72 levels in N2a cells and neurons, further suggesting UPS-mediated regulation. In rapamycin and BafA1-treated neurons, C9orf72 levels were significantly increased. Altogether, these findings corroborate the previously suggested regulatory role for C9orf72 in autophagy and suggest cell type-dependent regulation of C9orf72 levels via UPS and/or autophagy. Full article
(This article belongs to the Special Issue Autophagy in Neurodegenerative Diseases)
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Open AccessArticle
ER-Targeted Beclin 1 Supports Autophagosome Biogenesis in the Absence of ULK1 and ULK2 Kinases
Cells 2019, 8(5), 475; https://doi.org/10.3390/cells8050475 - 17 May 2019
Cited by 1
Abstract
Autophagy transports cytoplasmic material and organelles to lysosomes for degradation and recycling. Beclin 1 forms a complex with several other autophagy proteins and functions in the initiation phase of autophagy, but the exact role of Beclin 1 subcellular localization in autophagy initiation is [...] Read more.
Autophagy transports cytoplasmic material and organelles to lysosomes for degradation and recycling. Beclin 1 forms a complex with several other autophagy proteins and functions in the initiation phase of autophagy, but the exact role of Beclin 1 subcellular localization in autophagy initiation is still unclear. In order to elucidate the role of Beclin 1 localization in autophagosome biogenesis, we generated constructs that target Beclin 1 to the endoplasmic reticulum (ER) or mitochondria. Our results confirmed the proper organelle-specific targeting of the engineered Beclin 1 constructs, and the proper formation of autophagy-regulatory Beclin 1 complexes. The ULK kinases are required for autophagy initiation upstream of Beclin 1, and autophagosome biogenesis is severely impaired in ULK1/ULK2 double knockout cells. We tested whether Beclin 1 targeting facilitated its ability to rescue autophagosome formation in ULK1/ULK2 double knockout cells. ER-targeted Beclin 1 was most effective in the rescue experiments, while mitochondria-targeted and non-targeted Beclin 1 also showed an ability to rescue, but with lower activity. However, none of the constructs was able to increase autophagic flux in the knockout cells. We also showed that wild type Beclin 1 was enriched on the ER during autophagy induction, and that ULK1/ULK2 facilitated the ER-enrichment of Beclin 1 under basal conditions. The results suggest that one of the functions of ULK kinases may be to enhance Beclin 1 recruitment to the ER to drive autophagosome formation. Full article
(This article belongs to the Special Issue Autophagy in Neurodegenerative Diseases)
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Review

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Open AccessReview
Autophagic- and Lysosomal-Related Biomarkers for Parkinson’s Disease: Lights and Shadows
Cells 2019, 8(11), 1317; https://doi.org/10.3390/cells8111317 - 25 Oct 2019
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, for which no disease-modifying treatments exist. This lack of effective treatments is related to the advanced stage of neurodegeneration existing at the time [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, for which no disease-modifying treatments exist. This lack of effective treatments is related to the advanced stage of neurodegeneration existing at the time of diagnosis. Thus, the identification of early stage biomarkers is crucial. Biomarker discovery is often guided by the underlying molecular mechanisms leading to the pathology. One of the central pathways deregulated during PD, supported both by genetic and functional studies, is the autophagy-lysosomal pathway. Hence, this review presents different studies on the expression and activity of autophagic and lysosomal proteins, and their functional consequences, performed in peripheral human biospecimens. Although most biomarkers are inconsistent between studies, some of them, namely HSC70 levels in sporadic PD patients, and cathepsin D levels and glucocerebrosidase activity in PD patients carrying GBA mutations, seem to be consistent. Hence, evidence exists that the impairment of the autophagy-lysosomal pathway underlying PD pathophysiology can be detected in peripheral biosamples and further tested as potential biomarkers. However, longitudinal, stratified, and standardized analyses are needed to confirm their clinical validity and utility. Full article
(This article belongs to the Special Issue Autophagy in Neurodegenerative Diseases)
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Open AccessReview
Mitophagy in Parkinson’s Disease: From Pathogenesis to Treatment
Cells 2019, 8(7), 712; https://doi.org/10.3390/cells8070712 - 12 Jul 2019
Cited by 5
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease. The pathogenesis of PD is complicated and remains obscure, but growing evidence suggests the involvement of mitochondrial and lysosomal dysfunction. Mitophagy, the process of removing damaged mitochondria, is compromised in PD patients and [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disease. The pathogenesis of PD is complicated and remains obscure, but growing evidence suggests the involvement of mitochondrial and lysosomal dysfunction. Mitophagy, the process of removing damaged mitochondria, is compromised in PD patients and models, and was found to be associated with accelerated neurodegeneration. Several PD-related proteins are known to participate in the regulation of mitophagy, including PINK1 and Parkin. In addition, mutations in several PD-related genes are known to cause mitochondrial defects and neurotoxicity by disturbing mitophagy, indicating that mitophagy is a critical component of PD pathogenesis. Therefore, it is crucial to understand how these genes are involved in mitochondrial quality control or mitophagy regulation in the study of PD pathogenesis and the development of novel treatment strategies. In this review, we will discuss the critical roles of mitophagy in PD pathogenesis, highlighting the potential therapeutic implications of mitophagy regulation. Full article
(This article belongs to the Special Issue Autophagy in Neurodegenerative Diseases)
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Open AccessReview
Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery
Cells 2019, 8(6), 565; https://doi.org/10.3390/cells8060565 - 09 Jun 2019
Cited by 3
Abstract
Alpha-synuclein positive-intracytoplasmic inclusions are the common denominators of the synucleinopathies present as Lewy bodies in Parkinson’s disease, dementia with Lewy bodies, or glial cytoplasmic inclusions in multiple system atrophy. These neurodegenerative diseases also exhibit cellular dyshomeostasis, such as autophagy impairment. Several decades of [...] Read more.
Alpha-synuclein positive-intracytoplasmic inclusions are the common denominators of the synucleinopathies present as Lewy bodies in Parkinson’s disease, dementia with Lewy bodies, or glial cytoplasmic inclusions in multiple system atrophy. These neurodegenerative diseases also exhibit cellular dyshomeostasis, such as autophagy impairment. Several decades of research have questioned the potential link between the autophagy machinery and alpha-synuclein protein toxicity in synucleinopathy and neurodegenerative processes. Here, we aimed to discuss the active participation of autophagy impairment in alpha-synuclein accumulation and propagation, as well as alpha-synuclein-independent neurodegenerative processes in the field of synucleinopathy. Therapeutic approaches targeting the restoration of autophagy have started to emerge as relevant strategies to reverse pathological features in synucleinopathies. Full article
(This article belongs to the Special Issue Autophagy in Neurodegenerative Diseases)
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