TY - JOUR
T1 - Accelerated clinical disease and pathology in mucopolysaccharidosis type IIIB and GalNAc transferase double knockout mice
AU - Mohammed, Eman E.A.
AU - Snella, Elizabeth M.
AU - Rutz-Mendicino, Michelle M.
AU - Echevarria, Franklin D.
AU - Awedikian, Rafi
AU - Whitley, Elizabeth M.
AU - Ellinwood, N. Matthew
N1 - Funding Information:
We acknowledge funding from the Center for Integrated Animal Genomics of Iowa State University , the Lysosomal Storage Disease Research Consortium , and The Sanfilippo Children's Research Foundation . We thank Dr. Mark Sands for consultative support. We also wish to acknowledge the able animal care services of the Laboratory Animal Resources Office of Iowa State University.
PY - 2012/9
Y1 - 2012/9
N2 - Mucopolysaccharidosis type IIIB (MPS IIIB) is a neuropathic lysosomal storage disorder (LSD) resulting from an inherited deficiency of N-acetyl-α-d-glucosaminidase (Naglu) activity, an enzyme required to degrade the glycosaminoglycan heparan sulfate (HS). A deficiency in Naglu activity leads to lysosomal accumulation of HS as a primary storage substrate, and the gangliosides GM2 and GM3 as secondary accumulation products. To test the effect on neuropathogenesis of ganglioside accumulation, we bred mice deficient in both Naglu and GalNaAcT activities. The latter is the enzyme required for synthesis of GM2 and other complex gangliosides. Contrary to our expectation and to double knockout (DKO) studies where GalNAcT was knocked out in combination with other LSDs, our DKO mice showed a drastically shortened lifespan (24.5 ± 1.4 weeks, versus 50.5 ± 0.9 weeks (MPS IIIB), and 38.6 ± 1.2 weeks (GalNAcT)). To confirm that HS storage was the primary element resulting in the accelerated disease in our DKO mice, and not a locus tightly linked to the Naglu gene, we replicated our study with MPS IIIA mice, and found a virtually identical result (27.5 ± 1.8 weeks, versus 53.8 ± 1.6 weeks). All DKO mice showed motor signs of hind limb ataxia and hyper-extension, which were not seen in single KO or normal mice. At approximately 5. months of age, the MPS IIIB-DKO showed a unique pattern of vacuolization and nerve fiber degeneration in the corpus callosum, seen only in the DKO mice, as well as the relatively early intracytoplasmic vacuolation of many neurons and glia characteristic of the MPS IIIB mice. We analyzed motor performance on a rocking Rota-Rod beginning at 3. months of age. The MPS IIIA-DKO and MPS IIIB-DKO mice showed impaired performance and were statistically different from all parental lines. In particular, the MPS IIIB-DKO mice were significantly different from the parent MPS IIIB strains at 3, 5, and 6. months (p ≤ 0.0245). In conclusion we identified an accelerated phenotype associated with MPS IIIB within a DKO model system which showed white matter changes, with attendant performance deficits and a drastically shortened lifespan. This was in stark contrast to our expectations of a salutary response to the elimination of GM2. Despite this, the accelerated pathology and clinical signs represent a potentially improved system to study MPS IIIB neuropathogenesis as well as the role of complex gangliosides in normal CNS function.
AB - Mucopolysaccharidosis type IIIB (MPS IIIB) is a neuropathic lysosomal storage disorder (LSD) resulting from an inherited deficiency of N-acetyl-α-d-glucosaminidase (Naglu) activity, an enzyme required to degrade the glycosaminoglycan heparan sulfate (HS). A deficiency in Naglu activity leads to lysosomal accumulation of HS as a primary storage substrate, and the gangliosides GM2 and GM3 as secondary accumulation products. To test the effect on neuropathogenesis of ganglioside accumulation, we bred mice deficient in both Naglu and GalNaAcT activities. The latter is the enzyme required for synthesis of GM2 and other complex gangliosides. Contrary to our expectation and to double knockout (DKO) studies where GalNAcT was knocked out in combination with other LSDs, our DKO mice showed a drastically shortened lifespan (24.5 ± 1.4 weeks, versus 50.5 ± 0.9 weeks (MPS IIIB), and 38.6 ± 1.2 weeks (GalNAcT)). To confirm that HS storage was the primary element resulting in the accelerated disease in our DKO mice, and not a locus tightly linked to the Naglu gene, we replicated our study with MPS IIIA mice, and found a virtually identical result (27.5 ± 1.8 weeks, versus 53.8 ± 1.6 weeks). All DKO mice showed motor signs of hind limb ataxia and hyper-extension, which were not seen in single KO or normal mice. At approximately 5. months of age, the MPS IIIB-DKO showed a unique pattern of vacuolization and nerve fiber degeneration in the corpus callosum, seen only in the DKO mice, as well as the relatively early intracytoplasmic vacuolation of many neurons and glia characteristic of the MPS IIIB mice. We analyzed motor performance on a rocking Rota-Rod beginning at 3. months of age. The MPS IIIA-DKO and MPS IIIB-DKO mice showed impaired performance and were statistically different from all parental lines. In particular, the MPS IIIB-DKO mice were significantly different from the parent MPS IIIB strains at 3, 5, and 6. months (p ≤ 0.0245). In conclusion we identified an accelerated phenotype associated with MPS IIIB within a DKO model system which showed white matter changes, with attendant performance deficits and a drastically shortened lifespan. This was in stark contrast to our expectations of a salutary response to the elimination of GM2. Despite this, the accelerated pathology and clinical signs represent a potentially improved system to study MPS IIIB neuropathogenesis as well as the role of complex gangliosides in normal CNS function.
KW - Double knockout model
KW - GalNAc transferase
KW - Mucopolysaccharidosis type IIIB
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U2 - 10.1016/j.ymgme.2012.07.017
DO - 10.1016/j.ymgme.2012.07.017
M3 - Article
C2 - 22867887
AN - SCOPUS:84866150028
SN - 1096-7192
VL - 107
SP - 129
EP - 135
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1-2
ER -