European Journal of Experimental Biology Open Access

  • ISSN: 2248-9215
  • Journal h-index: 45
  • Journal CiteScore: 34.35
  • Average acceptance to publication time (5-7 days)
  • Average article processing time (30-45 days) Less than 5 volumes 30 days
    8 - 9 volumes 40 days
    10 and more volumes 45 days
Reach us +32 25889658

The contribution of mutant GBA alleles to the development of Parkinson′s disease in carriers of Gaucher disease mutations

International Conference on Glycobiology
September 21-22, 2017 HOUSTON, TX, USA

Mia Horowitz, Gali Maor, Olga Zalesca and Daniel Segal

Tel Aviv University, Israel

Posters & Accepted Abstracts: Eur J Exp Bio

Abstract:

Gaucher disease (GD) is an autosomal recessive disease resulting from mutations in the acid �?²-glucocerebrosidase (GCase) encoding gene, GBA, which leads to accumulation of glucosylceramide. GD patients and carriers of GD mutations have a significantly higher propensity to develop Parkinsonâ�?�?s disease (PD) in comparison to the non-GD population. This implies that mutant GBA allele is a predisposing factor for development of PD in carriers of GD mutations. We have previously shown that in cells that derived from patients of GD and carriers of GD mutations, mutant GCase molecules undergo ER retention, which leads to lead to ER stress and to activation of the unfolded protein response (UPR). We used Drosophila melanogaster to confirm that development of PD in carriers of GD mutations results from the presence of mutant GBA alleles. Drosophila has two GBA orthologs and each one of them has a mutant allele. We generated two different Drosophila models for carriers of GD mutations: Flies double heterozygous for the two-endogenous mutant GBA orthologs and flies expressing the human N370S or the L444P GCase variants. All lines exhibited UPR, death of dopaminergic cells, shorter life span and had a decreased negative geotaxis. ER stress and Parkinsonian signs could be rescued by growing the double heterozygous flies or flies containing the N370S or the L444P mutant GCase variants in the presence of the pharmacological chaperone ambroxol. Our results strongly suggest that the presence of a mutant GBA allele in dopaminergic cells leads to ER stress and to their death and contributes to development of Parkinsonâ�?�?s disease.