@article{3d4cb9dbb7374db7ac3a92b4c839e73e,
title = "Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course",
abstract = "Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/−). Survival analysis of 84 mice showed that in gba+/−//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.",
keywords = "Aggregates, Gaucher disease, Glucocerebrosidase, Mouse model, Parkinson disease, α-synuclein",
author = "Nahid Tayebi and Loukia Parisiadou and Bahafta Berhe and Gonzalez, {Ashley N.} and Jenny Serra-Vinardell and Tamargo, {Raphael J.} and Emerson Maniwang and Zachary Sorrentino and Hideji Fujiwara and Grey, {Richard J.} and Shahzeb Hassan and Blech-Hermoni, {Yotam N.} and Chuyu Chen and Ryan McGlinchey and Chrissy Makariou-Pikis and Mieu Brooks and Ginns, {Edward I.} and Ory, {Daniel S.} and Giasson, {Benoit I.} and Ellen Sidransky",
note = "Funding Information: This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health, and a grant from the National Institute of Neurological Disorders and Stroke (NS089622). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility (P30 DK020579) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985. Funding Information: This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health , and a grant from the National Institute of Neurological Disorders and Stroke ( NS089622 ). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility ( P30 DK020579 ) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985 . Publisher Copyright: {\textcopyright} 2017",
year = "2017",
month = dec,
doi = "10.1016/j.ymgme.2017.11.001",
language = "English (US)",
volume = "122",
pages = "198--208",
journal = "Biochemical Medicine and Metabolic Biology",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "4",
}
