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Updated: Jun 12, 2026
Using Caenorhabditis elegans as a Model System to Study Protein Homeostasis in a Multicellular Organism
Published on: December 18, 2013
Systemic characterization of aging-related phenotypes induced by wild-type and G2019S LRRK2 in Caenorhabditis elegans
Chun Li1, Fu-Yi Shi2, Xuan-Xuan He2
1Clinical Trial Research Center, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Mechanism and Quality of Chinese Medicine & Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China; Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China; Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, Sichuan, China.
Background:
Leucine-rich repeat kinase 2 (LRRK2), initially identified as a gene implicated in Parkinson's disease, is increasingly recognized for its influence on aging and associated disorders. However, its systemic roles in biological aging remain poorly understood.
Methods:
To assess its physiological roles, we utilized Caenorhabditis elegans models with pan-neuronal expression of either wild-type or G2019S-mutant human LRRK2. Aging-related phenotypes were evaluated through analyses of development, metabolic activity, oxidative stress response, behavior, neuronal integrity, and proteostasis. Transcriptomic and untargeted metabolomic profiling were conducted to elucidate the molecular consequences of LRRK2 expression and mutation.
Results:
Wild-type LRRK2 enhanced organismal growth, metabolic activity, and resistance to oxidative and heat stress, while simultaneously inducing mild neurodegenerative alterations. In contrast, the G2019S mutation substantially aggravated aging-associated phenotypes, including reduced lifespan, increased lipid and lipofuscin accumulation, and heightened dopaminergic vulnerability under stress conditions. Multi-omics analyses further showed that wild-type LRRK2 predominantly upregulated pathways related to energy metabolism and specific components of proteostasis, whereas G2019S resulted in diminished amino acid availability, disrupted protein homeostasis, and more pronounced metabolic dysregulation.
Conclusions:
Our findings support a bidirectional role of LRRK2 in aging: wild-type LRRK2 promotes systemic metabolic activation and stress resistance but increases neuronal susceptibility, while the G2019S mutation further amplifies metabolic and structural vulnerability. These effects are strongly tissue-dependent and modulated by mutational background. Collectively, this study expands the role of LRRK2 from a Parkinson's disease-associated protein to a multisystem regulator of aging, providing mechanistic insight and a basis for tissue-selective LRRK2-targeted interventions for age-related disorders.
Insights
Leucine-rich repeat kinase 2 (LRRK2) influences aging, with wild-type forms boosting metabolism and stress resistance but increasing neuronal risk. The G2019S mutation worsens aging phenotypes, highlighting LRRK2's complex role in aging and disease.
Area of Science:
- Aging Research
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and aging.
- Systemic roles of LRRK2 in biological aging are not well understood.
Purpose of the Study:
- To investigate the physiological roles of LRRK2 in aging using Caenorhabditis elegans.
- To elucidate the molecular mechanisms underlying LRRK2's impact on aging phenotypes.
Main Methods:
- Utilized C. elegans models expressing wild-type or G2019S-mutant human LRRK2.
- Evaluated aging phenotypes: development, metabolism, stress response, behavior, neuronal integrity, proteostasis.
- Conducted transcriptomic and metabolomic profiling.
Main Results:
- Wild-type LRRK2 enhanced growth, metabolism, and stress resistance but caused mild neurodegeneration.
- G2019S mutation reduced lifespan, increased lipid/lipofuscin accumulation, and heightened dopaminergic vulnerability.
- Multi-omics revealed distinct pathway alterations: WT LRRK2 upregulated energy metabolism/proteostasis; G2019S disrupted amino acid availability and protein homeostasis.
Conclusions:
- LRRK2 has a bidirectional role in aging: WT promotes metabolic activation/stress resistance but neuronal susceptibility; G2019S amplifies vulnerability.
- Effects are tissue-dependent and modulated by mutation.
- LRRK2 is a multisystem regulator of aging, offering targets for age-related disorders.
