Universität zu Köln

Woeste, Marina A., Stern, Sina, Raju, Diana N., Grahn, Elena, Dittmann, Dominik, Gutbrod, Katharina, Doermann, Peter, Hansen, Jan N., Schonauer, Sophie, Marx, Carina E., Hamzeh, Hussein, Koerschen, Heinz G., Aerts, Johannes M. F. G., Boenigk, Wolfgang, Endepols, Heike ORCID: 0000-0002-6166-4818, Sandhoff, Roger, Geyer, Matthias ORCID: 0000-0002-7718-5002, Berger, Thomas K., Bradke, Frank ORCID: 0000-0002-0345-3772 and Wachten, Dagmar (2019). Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. J. Biol. Chem., 294 (11). S. 3853 - 3872. ROCKVILLE: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

The nonlysosomal glucosylceramidase 2 (GBA2) catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. Mutations in the human GBA2 gene have been associated with hereditary spastic paraplegia (HSP), autosomal-recessive cerebellar ataxia (ARCA), and the Marinesco-Sjogren-like syndrome. However, the underlying molecular mechanisms are ill-defined. Here, using biochemistry, immunohistochemistry, structural modeling, and mouse genetics, we demonstrate that all but one of the spastic gait locus #46 (SPG46)-connected mutations cause a loss of GBA2 activity. We demonstrate that GBA2 proteins form oligomeric complexes and that protein-protein interactions are perturbed by some of these mutations. To study the pathogenesis of GBA2-related HSP and ARCA in vivo, we investigated GBA2-KO mice as a mammalian model system. However, these mice exhibited a high phenotypic variance and did not fully resemble the human phenotype, suggesting that mouse and human GBA2 differ in function. Whereas some GBA2-KO mice displayed a strong locomotor defect, others displayed only mild alterations of the gait pattern and no signs of cerebellar defects. On a cellular level, inhibition of GBA2 activity in isolated cerebellar neurons dramatically affected F-actin dynamics and reduced neurite outgrowth, which has been associated with the development of neurological disorders. Our results shed light on the molecular mechanism underlying the pathogenesis of GBA2-related HSP and ARCA and reveal species-specific differences in GBA2 function in vivo.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Woeste, Marina A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stern, Sina UNSPECIFIED UNSPECIFIED UNSPECIFIED Raju, Diana N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grahn, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Dittmann, Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutbrod, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Doermann, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, Jan N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schonauer, Sophie UNSPECIFIED UNSPECIFIED UNSPECIFIED Marx, Carina E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamzeh, Hussein UNSPECIFIED UNSPECIFIED UNSPECIFIED Koerschen, Heinz G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aerts, Johannes M. F. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boenigk, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Endepols, Heike UNSPECIFIED orcid.org/0000-0002-6166-4818 UNSPECIFIED Sandhoff, Roger UNSPECIFIED UNSPECIFIED UNSPECIFIED Geyer, Matthias UNSPECIFIED orcid.org/0000-0002-7718-5002 UNSPECIFIED Berger, Thomas K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bradke, Frank UNSPECIFIED orcid.org/0000-0002-0345-3772 UNSPECIFIED Wachten, Dagmar UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-153684
DOI:	10.1074/jbc.RA118.006311
Journal or Publication Title:	J. Biol. Chem.
Volume:	294
Number:	11
Page Range:	S. 3853 - 3872
Date:	2019
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication:	ROCKVILLE
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DISEASE; MICE; BETA-GLUCOSIDASE-2; IDENTIFICATION; CHOLESTEROL; INHIBITION; MIGLUSTAT; DEFECTS; THERAPY; ATAXIA Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15368