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Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease

Parkinson disease (PD) is a common neurodegenerative condition affecting people predominantly at old age that is characterized by a progressive loss of midbrain dopaminergic neurons and by the accumulation of α-synuclein-containing intraneuronal inclusions known as Lewy bodies. Defects in cellular d...

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Autores principales: Rahmani, Zohra, Surabhi, Satya, Rojo-Cortés, Francisca, Dulac, Amina, Jenny, Andreas, Birman, Serge
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657416/
https://www.ncbi.nlm.nih.gov/pubmed/36361864
http://dx.doi.org/10.3390/ijms232113078
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author Rahmani, Zohra
Surabhi, Satya
Rojo-Cortés, Francisca
Dulac, Amina
Jenny, Andreas
Birman, Serge
author_facet Rahmani, Zohra
Surabhi, Satya
Rojo-Cortés, Francisca
Dulac, Amina
Jenny, Andreas
Birman, Serge
author_sort Rahmani, Zohra
collection PubMed
description Parkinson disease (PD) is a common neurodegenerative condition affecting people predominantly at old age that is characterized by a progressive loss of midbrain dopaminergic neurons and by the accumulation of α-synuclein-containing intraneuronal inclusions known as Lewy bodies. Defects in cellular degradation processes such as the autophagy-lysosomal pathway are suspected to be involved in PD progression. The mammalian Lysosomal-associated membrane proteins LAMP1 and LAMP2 are transmembrane glycoproteins localized in lysosomes and late endosomes that are involved in autophagosome/lysosome maturation and function. Here, we show that the lack of Drosophila Lamp1, the homolog of LAMP1 and LAMP2, severely increased fly susceptibility to paraquat, a pro-oxidant compound known as a potential PD inducer in humans. Moreover, the loss of Lamp1 also exacerbated the progressive locomotor defects induced by the expression of PD-associated mutant α-synuclein A30P (α-synA30P) in dopaminergic neurons. Remarkably, the ubiquitous re-expression of Lamp1 in a mutant context fully suppressed all these defects and conferred significant resistance towards both PD factors above that of wild-type flies. Immunostaining analysis showed that the brain levels of α-synA30P were unexpectedly decreased in young adult Lamp1-deficient flies expressing this protein in comparison to non-mutant controls. This suggests that Lamp1 could neutralize α-synuclein toxicity by promoting the formation of non-pathogenic aggregates in neurons. Overall, our findings reveal a novel role for Drosophila Lamp1 in protecting against oxidative stress and α-synuclein neurotoxicity in PD models, thus furthering our understanding of the function of its mammalian homologs.
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spelling pubmed-96574162022-11-15 Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease Rahmani, Zohra Surabhi, Satya Rojo-Cortés, Francisca Dulac, Amina Jenny, Andreas Birman, Serge Int J Mol Sci Brief Report Parkinson disease (PD) is a common neurodegenerative condition affecting people predominantly at old age that is characterized by a progressive loss of midbrain dopaminergic neurons and by the accumulation of α-synuclein-containing intraneuronal inclusions known as Lewy bodies. Defects in cellular degradation processes such as the autophagy-lysosomal pathway are suspected to be involved in PD progression. The mammalian Lysosomal-associated membrane proteins LAMP1 and LAMP2 are transmembrane glycoproteins localized in lysosomes and late endosomes that are involved in autophagosome/lysosome maturation and function. Here, we show that the lack of Drosophila Lamp1, the homolog of LAMP1 and LAMP2, severely increased fly susceptibility to paraquat, a pro-oxidant compound known as a potential PD inducer in humans. Moreover, the loss of Lamp1 also exacerbated the progressive locomotor defects induced by the expression of PD-associated mutant α-synuclein A30P (α-synA30P) in dopaminergic neurons. Remarkably, the ubiquitous re-expression of Lamp1 in a mutant context fully suppressed all these defects and conferred significant resistance towards both PD factors above that of wild-type flies. Immunostaining analysis showed that the brain levels of α-synA30P were unexpectedly decreased in young adult Lamp1-deficient flies expressing this protein in comparison to non-mutant controls. This suggests that Lamp1 could neutralize α-synuclein toxicity by promoting the formation of non-pathogenic aggregates in neurons. Overall, our findings reveal a novel role for Drosophila Lamp1 in protecting against oxidative stress and α-synuclein neurotoxicity in PD models, thus furthering our understanding of the function of its mammalian homologs. MDPI 2022-10-28 /pmc/articles/PMC9657416/ /pubmed/36361864 http://dx.doi.org/10.3390/ijms232113078 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Rahmani, Zohra
Surabhi, Satya
Rojo-Cortés, Francisca
Dulac, Amina
Jenny, Andreas
Birman, Serge
Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease
title Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease
title_full Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease
title_fullStr Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease
title_full_unstemmed Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease
title_short Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease
title_sort lamp1 deficiency enhances sensitivity to α-synuclein and oxidative stress in drosophila models of parkinson disease
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657416/
https://www.ncbi.nlm.nih.gov/pubmed/36361864
http://dx.doi.org/10.3390/ijms232113078
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