Objective: The aim of the study was to understand how the E326K GBA1 mutation results in an increased risk for Parkinson disease, through influencing the relationship between glucocerebrosidase, alpha-synuclein and lipid metabolism.

Background: Mutations in the GBA1 gene are numerically the most important risk factor for Parkinson disease. The GBA1 gene encodes for the lysosomal hydrolase enzyme, glucocerebrosidase. GBA1 mutations often reduce glucocerebrosidase activity and lead to impairment of the autophagy-lysosomal pathway, which is important in the turnover of alpha-synuclein; accumulation of which is the key pathological hallmark of PD. The L444P and N370S mutations are common loss of function mutations. The E326K mutation is one of the most common GBA1 variants and is thought to have a minimal effect on glucocerebrosidase activity.

Method: The mutations investigated in this study are E326K, L444P and N370S. Fibroblasts homozygous and heterozygous for E326K were utilised, with homozygous fibroblasts for L444P and N370S, to understand the effect of E326K on glucocerebrosidase function compared to common pathogenic GBA1 mutations that can cause GD. Recombinant GBA1 proteins were over-expressed in SH-SY5Y neuroblastoma cells to investigate the effect of mutations on alpha-synuclein. The effect of E326K on lipid metabolism was assessed through visualisation of lipid droplets in cell lines. Some fibroblasts will be differentiated into midbrain dopamine neurons to assess the effect of E326K on glucocerebrosidase function.

Results: The results suggest that GBA1 mutations can act via both loss and gain of function pathways. The E326K mutation behaves differently to common pathogenic GBA1 mutations is not associated with significant loss of glucocerebrosidase activity or protein, endoplasmic reticulum retention or activation of the unfolded protein response. Despite this, the E326K mutation is associated with increased alpha-synuclein aggregates and accumulation of lipid droplets.

Conclusion: Mutations in the GBA1 gene are the most important genetic risk factor for Parkinson disease. Understanding the pathways associated with individual mutations may identify novel targets and pathways for improved therapeutics.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-gba1-mutations-in-the-relationship-between-gba1-and-alpha-synuclein-in-parkinson-disease/