Systemic characterization of aging-related phenotypes induced by wild-type and G2019S LRRK2 in Caenorhabditis elegans

  • Exp Neurol. 2026 Oct:404:115873. doi: 10.1016/j.expneurol.2026.115873.
Chun Li  1 ,  Fu-Yi Shi  2 ,  Xuan-Xuan He  2 ,  Shi-Ying Xiong  3 ,  Long Gu  4 ,  Gui-Sheng Wu  2 ,  Pan-Pan Hou  5 ,  Chen Huang  6 ,  Huai-Rong Luo  7
Affiliations
  • 1. Clinical 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.
  • 2. 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.
  • 3. 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.
  • 4. Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China; Department of Neurosurgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
  • 5. 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; Macau University of Science and Technology Innovation Technology Research Institute, Hengqin, Guangdong, China.
  • 6. 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. Electronic address: [email protected].
  • 7. 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. Electronic address: [email protected].
PMID: 42270006 DOI: 10.1016/j.expneurol.2026.115873
Abstract

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.

Keywords
Aging; Caenorhabditis elegans; LRRK2; Multi-omics; Nervous system.
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