The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA-induced Parkinson disease-like symptoms in the <i>Drosophila</i> brain

Issa, Abdul-Raouf; Sun, Jun; Petitgas, Céline; Mesquita, Anabela; Dulac, Amina; Robin, Marion; Mollereau, Bertrand; Jenny, Andreas; Chérif-Zahar, Baya; Birman, Serge

doi:10.1080/15548627.2018.1491489

Cited by 111 publications

(87 citation statements)

References 108 publications

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“…Previous studies have reported that Lamp2 confers stress resistance against various conditions, including acidosis, oxidative stress and neurodegenerative disorders (Saha, 2012;Damaghi et al, 2015;Qin et al, 2017;Issa et al, 2018) and is recognized as a vital protector against LMP with unclear underlying mechanisms (Geronimo-Olvera et al, 2017;Wiedmer et al, 2017). In our experimental system, OGD treatment caused the decline of Lamp2 and restoration of Lamp2 partially reduced LMP and cell death of cardiomyocytes.…”

Section: Discussionmentioning

confidence: 59%

“…The role of autophagy in ischemia and ischemia/reperfusion injury is still debated. Excessive inhibition of Beclin1 markedly increases cardiomyocyte death in response to hypoxia/reoxygenation injury (Issa et al, 2018). However, it has also been reported that different mechanisms to inhibit autophagy also protect against myocardial ischemia/reperfusion injury (Wu et al, 2018;Yu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

Cui

Zhao

et al. 2020

Front. Cell Dev. Biol.

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Lysosomal membrane permeabilization (LMP) has recently been recognized as an important cell death pathway in various cell types. However, studies regarding the correlation between LMP and cardiomyocyte death are scarce. Lysosomal membraneassociated protein 2 (Lamp2) is an important component of lysosomal membranes and is involved in both autophagy and LMP. In the present study, we found that the protein content of Lamp2 gradually decreased in response to oxygen, glucose and serum deprivation (OGD) treatment in vitro. To further elucidate its role in ischemic cardiomyocytes, particularly with respect to autophagy and LMP, we infected cardiomyocytes with adenovirus carrying full-length Lamp2 to restore its protein level in cells. We found that OGD treatment resulted in the occurrence of LMP and a decline in the viability of cardiomyocytes, which were remarkably reversed by Lamp2 restoration. Exogenous expression of Lamp2 also significantly alleviated the autophagic flux blockade induced by OGD treatment by promoting the trafficking of cathepsin B (Cat B) and cathepsin D (Cat D). Through drug intervention and gene regulation to alleviate and exacerbate autophagic flux blockade respectively, we found that impaired autophagic flux in response to ischemic injury contributed to the occurrence of LMP in cardiomyocytes. In conclusion, our present data suggest that Lamp2 overexpression can improve autophagic flux blockade probably by promoting the trafficking of cathepsins and consequently conferring cardiomyocyte resistance against lysosomal cell death (LCD) that is induced by ischemic injury. These results may indicate a new therapeutic target for ischemic heart damage.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

Cui

Zhao

et al. 2020

Front. Cell Dev. Biol.

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“…ROS detection in the Drosophila CNS was performed using the dihydroethidium (DHE) dye (Life technologies) following a previously described procedure (117,118). 10-day-old decapitated female flies were exposed to PQ for 90 min with or without (control) 30-min pretreatment with PACAP.…”

Section: Ros Measurementmentioning

confidence: 99%

Neuroprotective effects of PACAP against paraquat-induced oxidative stress in the Drosophila central nervous system

Hajji

Mteyrek

Sun

et al. 2019

Human Molecular Genetics

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Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that can arise after long-term exposure to environmental oxidative stressors, such as the herbicide paraquat (PQ). Here we investigated the potential neuroprotective action of vertebrate pituitary adenylate cyclase-activating polypeptide (PACAP) against PQ in Drosophila. We found that pretreatment with this neuropeptide applied to the ventral nerve cord (VNC) at low doses markedly extended the survival of wild-type decapitated flies exposed to neurotoxic levels of PQ or dopamine (DA). In contrast and interestingly, application of a PACAP receptor antagonist, PACAP-6-38, had opposite effects, significantly decreasing the resistance of flies to PQ. PACAP also reduced PQinduced caspase activation and reactive oxygen species (ROS) accumulation in the VNC. We then searched for the endogenous neuropeptide receptor potentially involved in PACAP-mediated neuroprotection in Drosophila. Knocking down the gene encoding the receptor Han/PDFR of the neuropeptide pigment-dispersing factor (PDF) in all neurons conferred to flies higher resistance to PQ, whereas PDFR downregulation restricted to PDF or DA neurons did not increase PQ resistance, but remarkably suppressed the neuroprotective action of PACAP. Further experiments performed with Pdf and Pdfr-deficient mutant strains confirmed that PDF and its receptor are required for PACAP-mediated neuroprotection in flies. We also provide evidence using split-GFP reconstitution that PDF neurons make synaptic contacts onto DA neurons in the abdominal VNC. Our results, therefore, suggest that the protective action of PACAP against PQ-induced defects in the Drosophila nervous system involves the modulation of PDFR signaling in a small number of interconnected neurons.

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“…Studies using Drosophila models have established a bewildering list of mechanisms involved in the α-syn pathogenicity. These mechanisms include alterations in the endoplasmic reticulum (ER)-Golgi trafficking and synaptic vesicle formation [ 133 , 134 ], glutathione abundance [ 111 ], glucose metabolism [ 135 ], actin cytoskeleton that leads to impaired mitochondrial dynamics [ 110 ], mitochondrial integrity and function [ 136 ], macroautophagy [ 137 ], and elevated oxidative stress levels [ 138 , 139 , 140 ].…”

Section: Genetic Models Of Sporadic Pdmentioning

confidence: 99%

Drosophila Models of Sporadic Parkinson’s Disease

Nagoshi

2018

IJMS

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Parkinson’s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress, aiming to provide mechanistic insights into the pathogenesis of PD. This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophila melanogaster and discusses their methodologies, new findings, and future perspectives.

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The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA-induced Parkinson disease-like symptoms in the Drosophila brain

Cited by 111 publications

References 108 publications

The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

The Lysosomal Membrane Protein Lamp2 Alleviates Lysosomal Cell Death by Promoting Autophagic Flux in Ischemic Cardiomyocytes

Neuroprotective effects of PACAP against paraquat-induced oxidative stress in the Drosophila central nervous system

Drosophila Models of Sporadic Parkinson’s Disease

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