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Glucocerebrosidase is shaking up the synucleinopathies

Marina Siebert, Ellen Sidransky, Wendy Westbroek
DOI: http://dx.doi.org/10.1093/brain/awu002 1304-1322 First published online: 15 February 2014

Summary

The lysosomal enzyme glucocerebrosidase, encoded by the glucocerebrosidase gene, is involved in the breakdown of glucocerebroside into glucose and ceramide. Lysosomal build-up of the substrate glucocerebroside occurs in cells of the reticulo-endothelial system in patients with Gaucher disease, a rare lysosomal storage disorder caused by the recessively inherited deficiency of glucocerebrosidase. Gaucher disease has a broad clinical phenotypic spectrum, divided into non-neuronopathic and neuronopathic forms. Like many monogenic diseases, the correlation between clinical manifestations and molecular genotype is not straightforward. There is now a well-established clinical association between mutations in the glucocerebrosidase gene and the development of more prevalent multifactorial disorders including Parkinson’s disease and other synucleinopathies. In this review we discuss recent studies advancing our understanding of the cellular relationship between glucocerebrosidase and α-synuclein, the potential impact of established and emerging therapeutics for Gaucher disease for the treatment of the synucleinopathies, and the role of lysosomal pathways in the pathogenesis of these neurodegenerative disorders.

  • glucocerebrosidase
  • α-synuclein
  • Gaucher disease
  • Parkinson’s disease
  • lysosome
  • Abbreviations
    CBE
    conduritol-B-epoxide
    ERAD
    endoplasmic reticulum-associated degradation
    GBA1
    glucocerebrosidase
    mTOR
    mammalian target of rapamycin
    PERK
    RNA-activated protein kinase-like endoplasmic reticulum kinase
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