Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2022

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

Résumé

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. - 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/).

Domaines

Neurobiologie
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Dates et versions

hal-03842311 , version 1 (07-11-2022)

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Zohra Rahmani, Satya Surabhi, Francisca Rojo-Cortés, Amina Dulac, Andreas Jenny, et al.. Lamp1 Deficiency Enhances Sensitivity to α-Synuclein and Oxidative Stress in Drosophila Models of Parkinson Disease. International Journal of Molecular Sciences, 2022, 23 (21), pp.13078. ⟨10.3390/ijms232113078⟩. ⟨hal-03842311⟩
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