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

Farfel-Becker, Tamar; Vitner, Einat; Dekel, Hani; Leshem, Noa; Berglin-Enquist, Ida LU ; Karlsson, Stefan LU and Futerman, Anthony H. (2009) In Human Molecular Genetics 18(8). p.1482-1488
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
18
issue
8
pages
1482 - 1488
publisher
Oxford University Press
external identifiers
  • wos:000264889800011
  • scopus:64549159732
ISSN
0964-6906
DOI
10.1093/hmg/ddp061
language
English
LU publication?
yes
id
176fa367-f102-4345-a3c7-91150dd6c53d (old id 1400616)
date added to LUP
2009-06-15 13:43:42
date last changed
2017-10-22 03:34:04
@article{176fa367-f102-4345-a3c7-91150dd6c53d,
  abstract     = {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.},
  author       = {Farfel-Becker, Tamar and Vitner, Einat and Dekel, Hani and Leshem, Noa and Berglin-Enquist, Ida and Karlsson, Stefan and Futerman, Anthony H.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {8},
  pages        = {1482--1488},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease},
  url          = {http://dx.doi.org/10.1093/hmg/ddp061},
  volume       = {18},
  year         = {2009},
}