TY - JOUR
T1 - Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC
AU - Marcò, Sara
AU - Pujol, Anna
AU - Roca, Carles
AU - Motas, Sandra
AU - Ribera, Albert
AU - Garcia, Miguel
AU - Molas, Maria
AU - Villacampa, Pilar
AU - Melia, Cristian S.
AU - Sánchez, Víctor
AU - Sanchez, Xavier
AU - Bertolin, Joan
AU - Ruberte, Jesús
AU - Haurigot, Virginia
AU - Bosch, Fatima
PY - 2016/9/1
Y1 - 2016/9/1
N2 - © 2016. Published by The Company of Biologists Ltd. Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease causedbydeficiency inactivityofthe transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.
AB - © 2016. Published by The Company of Biologists Ltd. Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease causedbydeficiency inactivityofthe transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.
KW - Animal model
KW - HGSNAT
KW - Lysosomal storage disease
KW - MPSIIIC
KW - Neurodegeneration
UR - https://ddd.uab.cat/record/185946
U2 - https://doi.org/10.1242/dmm.025171
DO - https://doi.org/10.1242/dmm.025171
M3 - Article
VL - 9
SP - 999
EP - 1013
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
SN - 1754-8403
IS - 9
ER -