McNeill, A; (2013) Glucocerebrosidase mutations and Parkinson's disease. Doctoral thesis , UCL (University College London).

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Abstract

Objectives - Gaucher disease (GD) is caused by bi-allelic mutations in the glucocerebrosidase gene (GBA). GD and heterozygous carriage of GBA mutations significantly increase the risk of developing Parkinson's disease (PD). Here we studied GD patients and carriers to identify a cohort of individuals with clinical signs of prodromal PD and generated fibroblast lines from them to study why GBA mutations cause PD. Methods - 83 patients with Type I GD and 41 of their heterozygous carrier relatives were recruited from lysosomal storage disorder clinics at the Royal Free Hospital and Addenbrooke's Hospital Cambridge, along with 30 mutation negative matched controls. They were clinically screened for hyposmia (University of Pennsylvania Smell Identification Test), cognitive impairment (Montreal Cognitive Assessment), autonomic dysfunction, REM sleep behaviour disorder and motor signs of PD. Two hundred and thirty cases of sporadic PD were screened for GBA gene mutations. Fibroblasts were generated from skin biopsies taken from a selection of patients. GBA metabolism (Western blotting for protein levels, enzyme activity, immunofluorescent localisation), mitochodrial metabolism, endoplasmic reticulum and oxidative stress markers were assayed in the cell lines. Results – GD patients and heterozygous carriers had significantly lower olfactory and cognitive function scores than controls. Several GD patients and carriers had motor signs of PD (e.g. rest tremor) while controls did not. Thirteen PD patients with heterozygous GBA mutations were identified. Their clinical phenotype was similar to mutation negative PD cases. GD fibroblast lines (n=5), and lines from heterozygous GBA mutation carriers with (n=4) and without PD (n=2) had reduced GBA enzyme activity due to endoplasmic reticulum retention of GBA protein. This was associated with upregulation of endoplasmic reticulum stress markers and oxidative stress (increased rate of dihydroethidium oxidation). Conclusions – a subset of GD patients and carriers express clinical markers of prodromal PD. Study of fibroblasts from these individuals indicates that endoplasmic reticulum and oxidative stress may contribute to increased PD risk in these individuals.

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