Mutations in
GBA1, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with
GBA1-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled
GBA1-associated PD by crossing
gba haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (
SNCAA53T), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether
gba+/−//
SNCAA53T mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of
gba+/−//
SNCAA53T (
n = 8),
SNCAA53T (
n = 9),
gba+/− (
n = 10) and wildtype (
n = 6) mice was evaluated between ages 8 and 23 months using the buried pellet test, novel object recognition test and the beam walk. Fifteen-month-old
gba+/−//
SNCAA53T mice showed more olfactory and motor deficits than wildtype mice. However, differences between
gba+/−//
SNCAA53T and
SNCAA53T mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while
gba haploinsufficiency leads to a more rapid demise, this might not result in an earlier prodromal stage, and other factors, including aging, oxidative stress and epigenetics, may contribute to the more fulminant disease course.
相似文献