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Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses

Vitner, Einat B.; Dekel, Hani; Zigdon, Hila; Shachar, Tamar; Farfel-Becker, Tamar; Eilam, Raya; Karlsson, Stefan LU and Futerman, Anthony H. (2010) In Human Molecular Genetics 19(18). p.3583-3590
Abstract
The neuronopathic forms of the human inherited metabolic disorder, Gaucher disease (GD), are characterized by severe neuronal loss, astrogliosis and microglial proliferation, but the cellular and molecular pathways causing these changes are not known. Recently, a mouse model of neuronopathic GD was generated in which glucocerebrosidase deficiency is limited to neural and glial progenitor cells. We now show significant changes in the levels and in the distribution of cathepsins in the brain of this mouse model. Cathepsin mRNA expression was significantly elevated by up to similar to 10-fold, with the time-course of the increase correlating with the progression of disease severity. Cathepsin activity and protein levels were also elevated.... (More)
The neuronopathic forms of the human inherited metabolic disorder, Gaucher disease (GD), are characterized by severe neuronal loss, astrogliosis and microglial proliferation, but the cellular and molecular pathways causing these changes are not known. Recently, a mouse model of neuronopathic GD was generated in which glucocerebrosidase deficiency is limited to neural and glial progenitor cells. We now show significant changes in the levels and in the distribution of cathepsins in the brain of this mouse model. Cathepsin mRNA expression was significantly elevated by up to similar to 10-fold, with the time-course of the increase correlating with the progression of disease severity. Cathepsin activity and protein levels were also elevated. Significant changes in cathepsin D distribution in the brain were detected, with cathepsin D elevated in areas where neuronal loss, astrogliosis and microgliosis were observed, such as in layer V of the cerebral cortex, the lateral globus pallidus and in various nuclei in the thalamus, brain regions known to be affected in the disease. Cathepsin D elevation was greatest in microglia and also noticeable in astrocytes. The distribution of cathepsin D was altered in neurons in a manner consistent with its release from the lysosome to the cytosol. Remarkably, ibubrofen treatment significantly reduced cathepsin D mRNA levels in the cortex of Gaucher mice. Finally, cathepsin levels were also altered in mouse models of a number of other sphingolipidoses. Our findings suggest the involvement of cathepsins in the neuropathology of neuronal forms of GD and of other lysosomal storage diseases, and are consistent with a crucial role for reactive microglia in neuronal degeneration in these diseases. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
19
issue
18
pages
3583 - 3590
publisher
Oxford University Press
external identifiers
  • wos:000281343600008
  • scopus:77956131970
ISSN
0964-6906
DOI
10.1093/hmg/ddq273
language
English
LU publication?
yes
id
5e1e60e4-4daa-433b-8dc9-dc052b838707 (old id 1672405)
date added to LUP
2010-09-23 14:27:49
date last changed
2018-05-29 10:49:10
@article{5e1e60e4-4daa-433b-8dc9-dc052b838707,
  abstract     = {The neuronopathic forms of the human inherited metabolic disorder, Gaucher disease (GD), are characterized by severe neuronal loss, astrogliosis and microglial proliferation, but the cellular and molecular pathways causing these changes are not known. Recently, a mouse model of neuronopathic GD was generated in which glucocerebrosidase deficiency is limited to neural and glial progenitor cells. We now show significant changes in the levels and in the distribution of cathepsins in the brain of this mouse model. Cathepsin mRNA expression was significantly elevated by up to similar to 10-fold, with the time-course of the increase correlating with the progression of disease severity. Cathepsin activity and protein levels were also elevated. Significant changes in cathepsin D distribution in the brain were detected, with cathepsin D elevated in areas where neuronal loss, astrogliosis and microgliosis were observed, such as in layer V of the cerebral cortex, the lateral globus pallidus and in various nuclei in the thalamus, brain regions known to be affected in the disease. Cathepsin D elevation was greatest in microglia and also noticeable in astrocytes. The distribution of cathepsin D was altered in neurons in a manner consistent with its release from the lysosome to the cytosol. Remarkably, ibubrofen treatment significantly reduced cathepsin D mRNA levels in the cortex of Gaucher mice. Finally, cathepsin levels were also altered in mouse models of a number of other sphingolipidoses. Our findings suggest the involvement of cathepsins in the neuropathology of neuronal forms of GD and of other lysosomal storage diseases, and are consistent with a crucial role for reactive microglia in neuronal degeneration in these diseases.},
  author       = {Vitner, Einat B. and Dekel, Hani and Zigdon, Hila and Shachar, Tamar and Farfel-Becker, Tamar and Eilam, Raya and Karlsson, Stefan and Futerman, Anthony H.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {18},
  pages        = {3583--3590},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses},
  url          = {http://dx.doi.org/10.1093/hmg/ddq273},
  volume       = {19},
  year         = {2010},
}