Abstract

Gaucher’s disease (GD) is the most prevalent lysosomal storage disorder. GD is caused by homozygous mutations of the GBA1 gene, which codes for beta-glucocerebrosidase (GCase). Although GD primarily affects peripheral tissues, the presence of neurological symptoms has been reported in several GD subtypes. GBA1 mutations have recently deserved increased attention upon the demonstration that both homo- and heterozygous GBA1 mutations represent the most important genetic risk factor for the appearance of synucleinopathies like Parkinson’s disease (PD) and dementia with Lewy bodies (LBD). Although reduced GCase activity leads to alpha-synuclein aggregation, the mechanisms sustaining a role for GCase in alpha-synuclein homeostasis still remain largely unknown. Furthermore, the role to be played by impairment in the physiological function of endoplasmic reticulum, mitochondria and other subcellular membranous components is currently under investigation. Here we focus on the impact of GCase loss-of-function that impact on the levels of sterylglucosides, molecules that are known to trigger a PD-related synucleinopathy upon administration in rats. Moreover, the concurrence of another gene also coding for an enzyme with GCase activity (GBA2 gene) should also be taken into consideration, bearing in mind that in addition to a hydrolytic function, both GCases also share transglycosylation as a second catalytic activity. Accordingly, sterylglycoside levels should also be considered to further assess their impact on the neurodegenerative process. In this regard—and besides GBA1 genotyping—we suggest that screening for GBA2 mutations should be considered, together with analytical measurements of cholesterol glycosides in body fluids, as biomarkers for both PD risk and disease progression.

Highlights

  • Glucocerebrosidases (GCases) catalyze the hydrolysis of D-glucosyl-N-acylsphingosine to D-glucose and N-acylsphingosine (E.C. enzyme entry: 3.2.1.45) and, the systematic name is D-glucosyl-N-acylsphingosine glucohydrolase

  • The link between GBA1 gene mutations and Parkinson’s disease (PD) is more likely due to a loss-of-function of GCase activity; loss-offunction is more usual in congenital diseases affecting enzyme genes and reduced enzyme activity the main cause of diseasepromoting alterations

  • The level of sterylglucosides and in particular of GlcChol, which are toxic upon accumulation, are controlled by both hydrolysis and transglucosylation activities of both GBA1e and GBA2e gene products

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Summary

INTRODUCTION

Glucocerebrosidases (GCases) catalyze the hydrolysis of D-glucosyl-N-acylsphingosine to D-glucose and N-acylsphingosine (E.C. enzyme entry: 3.2.1.45) and, the systematic name is D-glucosyl-N-acylsphingosine glucohydrolase. A further interesting fact is that the type of mutations may increase the risk of one given synucleinopathy In this regard and considering the two most frequent GBA1 mutations—L444P and N370S—the latter been regarded as more closely related to PD, whereas the L444P mutation seems to be more likely associated with LBD (Cilia et al, 2016). Other authors have reinforced the idea that GBA1 mutations contribute to alpha-synuclein aggregation and engagement of autophagy and lysosome-mediated processes (GCase is a lysosomal enzyme; Westbroek et al, 2011; Beavan and Schapira, 2013; Dehay et al, 2013; Manzoni and Lewis, 2013; Pan and Yue, 2014; Zhang et al, 2014; Magalhaes et al, 2016; García-Sanz et al, 2018; Kinghorn et al, 2017). Being obvious that alterations of a lysosomal enzyme may influence the handling of proteins such as synucleins and, engage autophagy, it is surely necessary to emit hypotheses aimed to better understand how a reduced enzyme activity may affect neuronal fate

REDUCED GCase ACTIVITY MAY LEAD TO NEUROTOXIC LEVELS OF STEROL GLYCOSIDES
Findings
ACHIEVING MECHANISTIC INSIGHTS
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