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

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Parkinson's disease (PD) is a progressive neurodegenerative disorder impacting millions globally, with no known cure.
• Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, aging, and environmental factors are established risk factors for PD.
• Investigating specific LRRK2 variants and their interaction with environmental stressors is crucial for understanding PD pathogenesis.

Purpose of the Study:

• To investigate the role of the human LRRK2 R1628P risk variant in inducing susceptibility to stress and triggering PD phenotypes.
• To establish and characterize a knock-in (KI) mouse model that mimics key aspects of human PD.

Main Methods:

• Generation of LRRK2 R1628P knock-in (KI) mice.
• Exposure of KI mice to stress insults (neurotoxin injections, chronic mild stress) at different ages.
• Assessment of behavioral and pathophysiological phenotypes, including locomotion, constipation, and dopamine-related protein levels.
• In vitro studies using primary neurons and fibroblasts from KI mice to assess oxidative stress susceptibility.

Main Results:

• KI mice exhibited key PD features, including locomotion impairment and increased constipation.
• Dopamine transporter (DAT) levels decreased, while dopamine levels increased in KI mouse brains.
• KI mouse-derived cells showed heightened susceptibility to oxidative stress.
• Environmental stresses exacerbated PD phenotypes in KI mice.

Conclusions:

• The LRRK2 R1628P KI mouse model effectively recapitulates progressive PD development.
• This model is valuable for studying the interplay between genetic predisposition (LRRK2 variant) and environmental factors in PD.
• The findings support the utility of this KI mouse line for preclinical research and therapeutic target identification in PD.