2. Academic Validation
  3. Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice

Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice

  • Int J Mol Sci. 2025 Apr 10;26(8):3556. doi: 10.3390/ijms26083556.
Zoë Bichler 1 2,  Sarivin Vanan 3 4 5,  Zhiwei Zhang 3,  Qianying Sally Dong 1,  Jolene Wei Ling Lee 3 6,  Chengwu Zhang 5,  Liting Hang 5,  Mei Jiang 3 7,  Parasuraman Padmanabhan 4,  Wuan Ting Saw 6 8,  Zhidong Zhou 6 8,  Balázs Gulyás 4,  Kah Leong Lim 4 5,  Li Zeng 3 4 6,  Eng King Tan 6 9 10
Affiliations

Affiliations

  • 1 Behavioural Neuroscience Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore.
  • 2 Center for Biometric Analysis, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • 3 Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore.
  • 4 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.
  • 5 Neurodegeneration Research Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore.
  • 6 Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore 169857, Singapore.
  • 7 Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, Department of Human Anatomy, Dongguan Campus, Guangdong Medical University, Dongguan 523808, China.
  • 8 Translational Therapeutics Lab, Research Department, National Neuroscience Institute, Singapore 169856, Singapore.
  • 9 Research Department, National Neuroscience Institute, Singapore General Hospital (SGH) Campus, Singapore 168581, Singapore.
  • 10 Department of Neurology, National Neuroscience Institute, Singapore 308433, Singapore.
PMID: 40332013 DOI: 10.3390/ijms26083556
Abstract

Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 10 million people worldwide, and for which no cure is currently known. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, age, as well as environmental factors such as neurotoxin exposure and stress, are known to increase the risk of developing the disease in humans. To investigate the role of a specific Asian variant of the LRRK2 gene to induce susceptibility to stress and trigger PD phenotypes with time, knock-in (KI) mice bearing the human LRRK2 R1628P risk variant have been generated and studied from 2 to 16 months of age in the presence (or absence) of stress insults, including neurotoxin injections and chronic mild stress applied at 3 months of age. Pathophysiological and behavioural phenotypes have been measured at different ages and primary neurons and fibroblast cells were cultured from the KI mouse line and treated with H2O2 to study susceptibility towards oxidative stress in vitro. KI mice displayed specific PD features and these phenotypes were aggravated by environmental stresses. In particular, KI mice developed locomotion impairment and increased constipation. In addition, dopamine-related proteins were dysregulated in KI mice brains: Dopamine Transporter (DAT) was decreased in the midbrain and striatum and dopamine levels were increased. Primary fibroblast cells and cortical neurons from KI mice also displayed increased susceptibility to oxidative stress. Therefore, the LRRK2 R1628P KI mice are an excellent model to study the progressive development of PD.

Keywords

Asian specific variant; LRRK2; Parkinson’s disease; behaviour; environmental toxins; oxidative stress; physiological stress.

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