Document Type
Article
Publication Date
4-10-2025
Original Citation
Bichler Z,
Vanan S,
Zhang Z,
Dong Q,
Lee J,
Zhang C,
Hang L,
Jiang M,
Padmanabhan P,
Saw W,
Zhou Z,
Gulyás B,
Lim K,
Zeng L,
Tan E.
Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice International Journal of Molecular Sciences. 2025;26(8):3556.
Keywords
JMG
JAX Source
International Journal of Molecular Sciences. 2025;26(8):3556.
DOI
https://doi.org/10.3390/ijms26083556
Grant
This research was supported by the NMRC Clinician Scientist Individual Research Grant (Grant Award Number: MOH-CIRG21nov-0001) and the Open Fund-Large Collaborative Grant (LCG002–SPARK II) provided by the Singapore Ministry of Health’s National Medical Re- search Council.
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder affecting nearly 10 mil- lion 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 pheno- types 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 dys- regulated 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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.