title: Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses.
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 approximately 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.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Einat B
authors.initials: EB
authors.lastname: Vitner
authors.forename: Hani
authors.initials: H
authors.lastname: Dekel
authors.forename: Hila
authors.initials: H
authors.lastname: Zigdon
authors.forename: Tamar
authors.initials: T
authors.lastname: Shachar
authors.forename: Tamar
authors.initials: T
authors.lastname: Farfel-Becker
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002403:Cathepsins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D013106:Sphingolipidoses / Q000235:genetics* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D002403:Cathepsins