Insights into post-translational processing of beta-galactosidase in an animal model resembling late infantile human G-gangliosidosis

Kreutzer, R; Kreutzer, M; Pröpsting, M J; Sewell, A C; Leeb, Tosso; Naim, H Y; Baumgärtner, W (2008). Insights into post-translational processing of beta-galactosidase in an animal model resembling late infantile human G-gangliosidosis. Journal of Cellular and Molecular Medicine, 12(5A), pp. 1661-1671. Wiley 10.1111/j.1582-4934.2007.00204.x

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G(M1)-gangliosidosis is a lysosomal storage disorder caused by a deficiency of ss-galactosidase activity. Human GM1-gangliosidosis has been classified into three forms according to the age of clinical onset and specific biochemical parameters. In the present study, a canine model for type II late infantile human GM1-gangliosidosis was investigated 'in vitro' in detail. For a better understanding of the molecular pathogenesis underlying G(M1)-gangliosidosis the study focused on the analysis of the molecular events and subsequent intracellular protein trafficking of beta-galactosidase. In the canine model the genetic defect results in exclusion or inclusion of exon 15 in the mRNA transcripts and to translation of two mutant precursor proteins. Intracellular localization, processing and enzymatic activity of these mutant proteins were investigated. The obtained results suggested that the beta-galactosidase C-terminus encoded by exons 15 and 16 is necessary for correct C-terminal proteolytic processing and enzyme activity but does not affect the correct routing to the lysosomes. Both mutant protein precursors are enzymatically inactive, but are transported to the lysosomes clearly indicating that the amino acid sequences encoded by exons 15 and 16 are necessary for correct folding and association with protective protein/cathepsin A, whereas the routing to the lysosomes is not influenced. Thus, the investigated canine model is an appropriate animal model for the human late infantile form and represents a versatile system to test gene therapeutic approaches for human and canine G(M1)-gangliosidosis.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

UniBE Contributor:

Leeb, Tosso

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health

ISSN:

1582-1838

Publisher:

Wiley

Language:

English

Submitter:

Tosso Leeb

Date Deposited:

17 Aug 2015 14:27

Last Modified:

17 Aug 2015 22:51

Publisher DOI:

10.1111/j.1582-4934.2007.00204.x

PubMed ID:

18088383

BORIS DOI:

10.7892/boris.70786

URI:

https://boris.unibe.ch/id/eprint/70786

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