Sex- and age-dependent control of dopamine function by LRRK2, and rapid reversal of dopamine release deficits in the LRRK2-G2019S knock-in mouse model of Parkinson's Disease.
- 1Montreal Neurological Institute, McGill University
Abstract
No disease-modifying therapy exists for Parkinson's disease (PD). At diagnosis (~65y), ~70% of nigrostriatal dopamine (DA) axons may have degenerated, so identifying when and how striatal axon function declines is critical. LRRK2 hyperactivity is observed in LRRK2 and VPS35 familial cases, and also idiopathic PD. Thus suggests LRRK2 hyperfunction is a common pathophysiological feature of PD. LRRK2 inhibitors are currently in human trials, yet their effects on brain circuit function are poorly characterized. By optical imaging of iGluSnFR and dLight we measured striatal glutamate and DA release in WT, LRRK2 G2019S (LKI) and VPS35 D620N (VKI) knock-in mice, across adult ages and sexes, with and without LRRK2 inhibition. In WT mice, ongoing LRRK2 activity regulated DA release in an age- and sex-dependent manner. Acute inhibition reversed basal sex differences in striatal glutamate and DA release in aged mice, and potentiated DA release more in middle-aged females than males. In LKI mice, DA release declined progressively, first in males, then females, after maturation to full adulthood, and remained impaired in very old LKI and VKI mice. Release deficits in aged LKI and VKI mice were resistant to acute LRRK2 inhibition, but 2h inhibition rapidly reversed deficits in middle-aged LKI males and females. We conclude that LRRK2 activity, and inhibition effects, depend on age, sex, and genotype, with direct implications for the design and timing of current LRRK2 inhibitor clinical trials for PD.
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BibTeX
@misc{gentle2026agedependent,
title = {{Sex- and age-dependent control of dopamine function by LRRK2, and rapid reversal of dopamine release deficits in the LRRK2-G2019S knock-in mouse model of Parkinson's Disease.}},
author = {C. Gentle and A. Kamesh and J. F. Madranges and S. Coady and B. F. J. Vieira and C. T. Ribeiro and S. McClean and N. Kuhlmann and A. Khayachi and A. Pietrantonio and L. Moulanier and E. Cohen and M. J. Farrer and M. Parsons and A. Milnerwood},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.14.759167},
url = {https://www.biorxiv.org/content/10.64898/2026.10.14.759167v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Sex- and age-dependent control of dopamine function by LRRK2, and rapid reversal of dopamine release deficits in the LRRK2-G2019S knock-in mouse model of Parkinson's Disease.
AU - C. Gentle
AU - A. Kamesh
AU - J. F. Madranges
AU - S. Coady
AU - B. F. J. Vieira
AU - C. T. Ribeiro
AU - S. McClean
AU - N. Kuhlmann
AU - A. Khayachi
AU - A. Pietrantonio
AU - L. Moulanier
AU - E. Cohen
AU - M. J. Farrer
AU - M. Parsons
AU - A. Milnerwood
PY - 2026
DA - 2026/10/14
PB - bioRxiv
DO - 10.64898/2026.10.14.759167
UR - https://www.biorxiv.org/content/10.64898/2026.10.14.759167v1
AB - No disease-modifying therapy exists for Parkinson's disease (PD). At diagnosis (~65y), ~70% of nigrostriatal dopamine (DA) axons may have degenerated, so identifying when and how striatal axon function declines is critical. LRRK2 hyperactivity is observed in LRRK2 and VPS35 familial cases, and also idiopathic PD. Thus suggests LRRK2 hyperfunction is a common pathophysiological feature of PD. LRRK2 inhibitors are currently in human trials, yet their effects on brain circuit function are poorly characterized. By optical imaging of iGluSnFR and dLight we measured striatal glutamate and DA release in WT, LRRK2 G2019S (LKI) and VPS35 D620N (VKI) knock-in mice, across adult ages and sexes, with and without LRRK2 inhibition. In WT mice, ongoing LRRK2 activity regulated DA release in an age- and sex-dependent manner. Acute inhibition reversed basal sex differences in striatal glutamate and DA release in aged mice, and potentiated DA release more in middle-aged females than males. In LKI mice, DA release declined progressively, first in males, then females, after maturation to full adulthood, and remained impaired in very old LKI and VKI mice. Release deficits in aged LKI and VKI mice were resistant to acute LRRK2 inhibition, but 2h inhibition rapidly reversed deficits in middle-aged LKI males and females. We conclude that LRRK2 activity, and inhibition effects, depend on age, sex, and genotype, with direct implications for the design and timing of current LRRK2 inhibitor clinical trials for PD.
ER -