Journal Article

DZNE-2020-07559

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46).

Sultana, S. ; Reichbauer, J.DZNE* ; Schüle, R.DZNE* ; Mochel, F. ; Synofzik, M.DZNE* ; van der Spoel, A. C. (Corresponding author)

2015
Academic Press Orlando, Fla.

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Please use a persistent id in citations: doi:10.1016/j.bbrc.2015.07.112

Abstract: Glucosylceramide is a membrane glycolipid made up of the sphingolipid ceramide and glucose, and has a wide intracellular distribution. Glucosylceramide is degraded to ceramide and glucose by distinct, non-homologous enzymes, including glucocerebrosidase (GBA), localized in the endolysosomal pathway, and β-glucosidase 2 (GBA2), which is associated with the plasma membrane and/or the endoplasmic reticulum. It is well established that mutations in the GBA gene result in endolysosomal glucosylceramide accumulation, which triggers Gaucher disease. In contrast, the biological significance of GBA2 is less well understood. GBA2-deficient mice present with male infertility, but humans carrying mutations in the GBA2 gene are affected with a combination of cerebellar ataxia and spastic paraplegia, as well as with thin corpus callosum and cognitive impairment (SPastic Gait locus #46, SPG46). To improve our understanding of the biochemical consequences of the GBA2 mutations, we have evaluated five nonsense and five missense GBA2 mutants for their enzyme activity. In transfected cells, the mutant forms of GBA2 were present in widely different amounts, ranging from overabundant to very minor, compared to the wild type enzyme. Nevertheless, none of the GBA2 mutant cDNAs raised the enzyme activity in transfected cells, in contrast to the wild-type enzyme. These results suggest that SPG46 patients have a severe deficit in GBA2 activity, because the GBA2 mutants are intrinsically inactive and/or reduced in amount. This assessment of the expression levels and enzyme activities of mutant forms of GBA2 offers a first insight in the biochemical basis of the complex pathologies seen in SPG46.

Keyword(s): Glucosylceramidase (MeSH) ; Animals (MeSH) ; COS Cells (MeSH) ; Cell Line, Tumor (MeSH) ; Cerebellar Ataxia: enzymology (MeSH) ; Cerebellar Ataxia: genetics (MeSH) ; Cerebellar Ataxia: pathology (MeSH) ; Endoplasmic Reticulum: enzymology (MeSH) ; Endoplasmic Reticulum: pathology (MeSH) ; Enzyme Assays (MeSH) ; Gene Expression Regulation (MeSH) ; HeLa Cells (MeSH) ; Humans (MeSH) ; Lysosomes: enzymology (MeSH) ; Lysosomes: pathology (MeSH) ; Mutation (MeSH) ; Neurons: enzymology (MeSH) ; Neurons: pathology (MeSH) ; Plasmids: chemistry (MeSH) ; Plasmids: metabolism (MeSH) ; Signal Transduction (MeSH) ; Spastic Paraplegia, Hereditary: enzymology (MeSH) ; Spastic Paraplegia, Hereditary: genetics (MeSH) ; Spastic Paraplegia, Hereditary: pathology (MeSH) ; Transfection (MeSH) ; Transgenes (MeSH) ; beta-Glucosidase: deficiency (MeSH) ; beta-Glucosidase: genetics (MeSH) ; beta-Glucosidase ; GBA2 protein, human

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser 1)
2. Functional Neurogeriatrics (AG Maetzler)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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