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No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease

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Author

  • Tamar Farfel-Becker
  • Einat Vitner
  • Hani Dekel
  • Noa Leshem
  • Ida Berglin-Enquist
  • Stefan Karlsson
  • Anthony H. Futerman

Summary, in English

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by defects in the activity of the lysosomal enzyme, glucocerebrosidase, resulting in intracellular accumulation of glucosylceramide (GlcCer). Neuronopathic forms, which comprise only a small percent of GD patients, are characterized by neurological impairment and neuronal cell death. Little is known about the pathways leading from GlcCer accumulation to neuronal death or dysfunction but defective calcium homeostasis appears to be one of the pathways involved. Recently, endoplasmic reticulum stress together with activation of the unfolded protein response (UPR) has been suggested to play a key role in cell death in neuronopathic forms of GD, and moreover, the UPR was proposed to be a common mediator of apoptosis in LSDs (Wei et al. (2008) Hum. Mol. Genet. 17, 469-477). We now systematically examine whether the UPR is activated in neuronal forms of GD using a selection of neuronal disease models and a combination of western blotting and semi-quantitative and quantitative real-time polymerase chain reaction. We do not find any changes in either protein or mRNA levels of a number of typical UPR markers including BiP, CHOP, XBP1, Herp and GRP58, in either cultured Gaucher neurons or astrocytes, or in brain regions from mouse models, even at late symptomatic stages. We conclude that the proposition that the UPR is a common mediator for apoptosis in all neurodegenerative LSDs needs to be re-evaluated.

Publishing year

2009

Language

English

Pages

1482-1488

Publication/Series

Human Molecular Genetics

Volume

18

Issue

8

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Medical Genetics

Status

Published

ISBN/ISSN/Other

  • ISSN: 0964-6906