Behavioral Phenotyping in a Murine Model of <i>GBA1</i>-Associated Parkinson Disease

• Main Authors: Jenny Do, Gani Perez, Bahafta Berhe, Nahid Tayebi, Ellen Sidransky
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: International Journal of Molecular Sciences
• Subjects: Gaucher disease; <i>GBA1</i>; Parkinson disease; mouse model; buried pellet test; novel object recognition
• Online Access: https://www.mdpi.com/1422-0067/22/13/6826
• ISSN: 1661-6596; 1422-0067

Mutations in <i>GBA1</i>, the gene encoding glucocerebrosidase, are common genetic risk factors for Parkinson disease (PD). While the mechanism underlying this relationship is unclear, patients with <i>GBA1</i>-associated PD often have an earlier onset and faster progression than idiopathic PD. Previously, we modeled <i>GBA1</i>-associated PD by crossing <i>gba</i> haploinsufficient mice with mice overexpressing a human mutant α-synuclein transgene (<i>SNCA^A53T</i>), observing an earlier demise, shorter life span and faster symptom progression, although behavioral testing was not performed. To assess whether <i>gba^{<span style="font-variant: small-caps;">+</span>}</i>^{<span style="font-variant: small-caps;">/−</span>}//<i>SNCA^A53T</i> mice exhibit a prodromal behavioral phenotype, we studied three cardinal PD features: olfactory discrimination, memory dysfunction, and motor function. The longitudinal performance of <i>gba⁺</i>^/<i>−</i>//<i>SNCA^A53T</i> (<i>n</i> = 8), <i>SNCA^A53T</i> (<i>n</i> = 9), <i>gba⁺</i>^/<i>−</i> (<i>n</i> = 10) and wildtype (<i>n</i> = 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 <i>gba⁺</i>^/<i>−</i>//<i>SNCA^A53T</i> mice showed more olfactory and motor deficits than wildtype mice. However, differences between <i>gba⁺</i>^/<i>−</i>//<i>SNCA^A53T</i> and <i>SNCA^A53T</i> mice generally did not reach statistical significance, possibly due to small sample sizes. Furthermore, while <i>gba</i> 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.