Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease
Muñoz-Juan, Amanda (Institut de Ciència de Materials de Barcelona)
Benseny Cases, Núria (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Guha, Sanjib (Nautilus Biotechnology)
Barba, Ignasi (Universitat de Vic)
Caldwell, K A (The University of Alabama System)
Caldwell, G A (The University of Alabama System)
Agulló, Laura (Universitat de Vic. Universitat Central de Catalunya)
Yuste Mateos, Víctor José (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Laromaine, Anna (Institut de Ciència de Materials de Barcelona)
Dalfo, Esther (Universitat Autònoma de Barcelona. Institut de Neurociències)

Date:	2024
Abstract:	Patients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor and non-motor symptoms correlate with progressive deposition of the protein alpha-synuclein (Asyn) both within and outside of the central nervous system, and its accumulation parallels neurodegeneration. The genome of Caenorhabditis elegans does not encode a homolog of Asyn, thus rendering this nematode an invaluable system with which to investigate PD-related mechanisms in the absence of interference from endogenous Asyn aggregation. CED-10 is the nematode homolog of human RAC1, a small GTPase needed to maintain the function and survival of dopaminergic neurons against human Asyn-induced toxicity in C. elegans. Here, we introduce C. elegans RAC1/ced-10 mutants as a predictive tool to investigate early PD symptoms before neurodegeneration occurs. Deep phenotyping of these animals reveals that, early in development, they displayed altered defecation cycles, GABAergic abnormalities and an increased oxidation index. Moreover, they exhibited altered lipid metabolism evidenced by the accumulation of lipid droplets. Lipidomic fingerprinting indicates that phosphatidylcholine and sphingomyelin, but not phosphatidylethanolamine or phosphatidylserine, were elevated in RAC1/ced-10 mutant nematodes. These collective characteristics reflect the non-motor dysfunction, GABAergic neurotransmission defects, upregulation of stress response mechanisms, and metabolic changes associated with early-onset PD. Thus, we put forward an easy-to-manipulate preclinical animal model to deepen our understanding of early-stage PD and accelerate the translational path for therapeutic target discovery.
Grants:	Instituto de Salud Carlos III PH613883 Agencia Estatal de Investigación RTI2018-096273-B-I00 Agencia Estatal de Investigación PID2021-122645OB-100 Agencia Estatal de Investigación CEX2019-000917 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-765 Ministerio de Ciencia, Innovación y Universidades FPU18/05190
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Early diagnosis RAC1/ced-10 nematodes ; Early-Parkinson's disease ; GABAergic impairment ; Lipid metabolism
Published in:	Progress in neurobiology, Vol. 234 (March 2024) , art. 102572, ISSN 1873-5118

DOI: 10.1016/j.pneurobio.2024.102572
PMID: 38253120

14 p, 7.8 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles