Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease

Amanda Muñoz-Juan, N Benseny-Cases, S Guha, Ignasi Barba, KA Caldwell, GA Caldwell, L Agulló, VJ Yuste, A Laromaine, Esther Dalfo

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)
1 Downloads (Pure)

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.
Original languageEnglish
Article number102572
JournalProgress in Neurobiology
Volume234
Early online date20 Jan 2024
DOIs
Publication statusPublished - Mar 2024

Keywords

  • Early diagnosis RAC1/ced-10 nematodes
  • Early-Parkinson's disease
  • GABAergic impairment
  • Lipid metabolism

Fingerprint

Dive into the research topics of 'Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson's disease'. Together they form a unique fingerprint.

Cite this