Abstract
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.
Highlights
Parkinson disease (PD) is a late-onset neurodegenerative disorder with a complex etiology, afflicting 2% of the population over age 65 worldwide [1,2]
This study characterized the age-related behavior and motor function in gba+/ − //SNCAA53T. Mice compared to their controls, with the goal of evaluating whether earlier disease manifestations were apparent in gba+/ − //SNCAA53T mice, analogous to the prodromal signs observed in patients with GBA1-associated PD
Discerning PD early in the disease course could aid in identifying disease biomarkers, and in understanding the disease pathogenesis
Summary
Parkinson disease (PD) is a late-onset neurodegenerative disorder with a complex etiology, afflicting 2% of the population over age 65 worldwide [1,2]. It is primarily characterized by bradykinesia and tremor, and the pathological finding of Lewy bodies in the substantia nigra and brainstem. Impaired or deficient GCase leads to its inability to cleave its native lipid substrates, glucosylceramide (GluCer) and glucosylsphingosine (GluSph), into recyclable moieties. This results in their toxic accumulation in the lysosome, leading to a wide range of symptoms [9]
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