Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options

Giovedì, Silvia; Ravanelli, Margherita Maria; Parisi, Barbara; Bettegazzi, Barbara; Guarnieri, Fabrizia C.

doi:10.3389/fncel.2020.602116

Cited by 32 publications

(31 citation statements)

References 147 publications

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“…The implication of mitochondrial dysfunction was the earliest mechanistic insight into PD pathogenesis, however, an increasing amount of evidence is indicative of an important role of the endo-lysosomal pathway in PD [ 120 , 121 , 122 ]. The endo-lysosomal pathway is important for protein homeostasis and consists of endocytosis, retromer and autolysosome [ 123 , 124 , 125 ] that we will separately discuss. PD-related proteins that are linked to one or more of these processes are alpha-synuclein, VPS35 and LRRK2 that cause autosomal dominant forms of PD ( Figure 3 ).…”

Section: Endo-lysosomal Pd Connection In Drosophila Melamentioning

confidence: 99%

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

Vos

Klein

2021

Cells

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

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Section: Endo-lysosomal Pd Connection In Drosophila Melamentioning

confidence: 99%

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

Vos

Klein

2021

Cells

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“…Hence ER stress signaling to restore homeostasis acts to both renature proteins and simultaneously to facilitate the break down excess protein load via autophagy. In AD the clearance of amyloid-β plaques can be mediated via autophagy, which correlates with improved in vivo mouse memory function [ 22 , 24 ]. Similar in vitro and in vivo findings to amyloid-β have been made for ALS aggregates and mutant Huntingtin aggregates [ 21 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43

Dent

Booth

Roberts

et al. 2021

Aging

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Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer’s Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.

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“…Aberrant autophagy including hyperactive autophagy induction, defective AP formation, or dysfunction of AP maturation could result in protein aggregation and finally neuronal death. Abnormal autophagy has been found in several neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as ALS 3 , 13 – 15 .…”

Section: Introductionmentioning

confidence: 99%

Simvastatin accelerated motoneurons death in SOD1G93A mice through inhibiting Rab7-mediated maturation of late autophagic vacuoles

Bai

Wen

et al. 2021

Cell Death Dis

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by motoneuron loss, for which there is currently no effective treatment. Statins, as inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, are used as drugs for treatment for a variety of disease such as ischemic diseases, neurodegenerative diseases, cancer, and inflammation. However, our previous evidence has demonstrated that simvastatin leads to cytotoxicity in NSC34-hSOD1G93A cells by aggravating the impairment of autophagic flux, but the role of simvastatin in ALS model remains elusive. In present study, we reported that after simvastatin treatment, SOD1G93A mice showed early onset of the disease phenotype and shortened life span, with aggravated autophagic flux impairment and increased aggregation of SOD1 protein in spinal cord motoneurons (MNs) of SOD1G93A mice. In addition, simvastatin repressed the ability of Rab7 localization on the membrane by inhibiting isoprenoid synthesis, leading to impaired late stage of autophagic flux rather than initiation. This study suggested that simvastatin significantly worsened impairment of late autophagic flux, resulting in massive MNs death in spinal cord and accelerated disease progression of SOD1G93A mice. Together, these findings might imply a potential risk of clinic application of statins in ALS.

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Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options

Cited by 32 publications

References 147 publications

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

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

Inhibition of heat shock proteins increases autophagosome formation, and reduces the expression of APP, Tau, SOD1 G93A and TDP-43

Simvastatin accelerated motoneurons death in SOD1G93A mice through inhibiting Rab7-mediated maturation of late autophagic vacuoles

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