Age- and Sex-Dependent Behavioral and Neurochemical Alterations in hLRRK2-G2019S BAC Mice.

Abstract

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with late-onset Parkinson's disease (PD). Although PD affects men and women differently, longitudinal studies examining sex- and age-dependent alterations in mice carrying the G2019S mutation are limited. We examined if behavioral and neurochemical dysfunctions, as well as neurodegeneration, occur in male and female BAC LRRK2-hG2019S (G2019S) mice, compared to their age-matched wild type littermates, at four age ranges. In the open field test, hyperlocomotion was observed in 10-12 month old male and 2-4.5 months old female G2019S mice. In the pole test, motor coordination was impaired in male G2019S mice from 15 months of age and in 20-21 months old female G2019S mice. In the striatum of G2019S male and female mice, the amounts of tyrosine hydroxylase (TH), measured with Western blotting, were unaltered. However, we found a decreased expression of the dopamine transporter in 20-21 month old male G2019S mice. The number of TH-positive neurons in the substantia nigra compacta was unaltered in 20-21 month old male and female G2019S mice. These results identify sex- and age-dependent differences in the occurrence of motor and neurochemical deficits in BAC LRRK2-hG2019S mice, and no degeneration of DA neurons.