A novel conditional Sgsh knockout mouse model recapitulates phenotypic and neuropathic deficits of Sanfilippo syndrome.

Autor: Lau AA; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia. adeline.lau@sahmri.com., King BM; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Thorsen CL; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Hassiotis S; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Beard H; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Trim PJ; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Whyte LS; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Tamang SJ; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Duplock SK; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Snel MF; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Hopwood JJ; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia., Hemsley KM; Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute (SAHMRI), PO Box 11060, Adelaide, SA, 5001, Australia.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2017 Sep; Vol. 40 (5), pp. 715-724. Date of Electronic Publication: 2017 Apr 27.
DOI: 10.1007/s10545-017-0044-4
Abstrakt: Mucopolysaccharidosis (MPS) type IIIA, or Sanfilippo syndrome, is a neurodegenerative lysosomal storage disorder caused by a deficiency of the lysosomal enzyme N-sulfoglucosamine sulfohydrolase (SGSH), involved in the catabolism of heparan sulfate. The clinical spectrum is broad and the age of symptom onset and the degree of preservation of cognitive and motor functions appears greatly influenced by genotype. To explore this further, we generated a conditional knockout (Sgsh KO ) mouse model with ubiquitous Sgsh deletion, and compared the clinical and pathological phenotype with that of the spontaneous Sgsh D31N MPS-IIIA mouse model. Phenotypic deficits were noted in Sgsh KO mice prior to Sgsh D31N mice, however these outcomes did not correlate with any shift in the time of appearance nor rate of accumulation of primary (heparan sulfate) or secondary substrates (GM2/GM3 gangliosides). Other disease lesions (elevations in lysosomal integral membrane protein-II expression, reactive astrocytosis and appearance of ubiquitin-positive inclusions) were also comparable between affected mouse strains. This suggests that gross substrate storage and these neuropathological markers are neither primary determinants, nor good biomarkers/indicators of symptom generation, confirming similar observations made recently in MPS-IIIA patients. The Sgsh KO mouse will be a useful tool for elucidation of the neurological basis of disease and assessment of the clinical efficacy of new treatments for Sanfilippo syndrome.
Databáze: MEDLINE
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