Crawley Allison C, Gliddon Briony L, Auclair Dyane, Brodie Suzanne L, Hirte Craig, King Barbara M, Fuller Maria, Hemsley Kim M, Hopwood John J
Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, SA 5006, South Australia.
Brain Res. 2006 Aug 9;1104(1):1-17. doi: 10.1016/j.brainres.2006.05.079. Epub 2006 Jul 7.
The original mucopolysaccharidosis type IIIA (MPS IIIA) mice were identified in a mixed background with contributions from four different strains. To ensure long-term stability and genetic homogeneity of this lysosomal storage disease (LSD) model, the aim of this study was to develop and characterize a C57BL/6 congenic strain. The B6.Cg-Sgsh(mps3a) strain compares favorably with the original mixed donor strain, exhibiting low liver sulfamidase activity and significant brain heparan sulfate-derived disaccharide elevation from birth. A rapid increase in brain disaccharide levels occurred after birth, with a plateau reached by 13 weeks of age at 110x the levels observed in brains of age-matched unaffected mice. Typical lysosomal inclusions were observed in cerebral cortical and cerebellar neurons and in liver hepatocytes and Kupffer cells. Ubiquitin-positive spheroids and GM(2)-ganglioside were also detected in brain. Using the Morris water maze in male mice, impaired memory and spatial learning was evident at 20 weeks of age in B6.Cg-Sgsh(mps3a) MPS IIIA mice. Other behavioral changes include motor, cognitive and sensory deficits, and aggression. Male B6.Cg-Sgsh(mps3a) MPS IIIA mice exhibited more behavioral abnormalities than B6.Cg-Sgsh(mps3a) MPS IIIA females, as observed previously in the original mixed background strain. Affected mice generally survive to 9 to 12 months of age, before death or euthanasia for humane reasons. Overall, minor differences were apparent between the new congenic and previously described mixed MPS IIIA strains. Availability of an in-bred strain will ensure more reproducible experimental outcomes thereby assisting in our goal of developing effective therapies for LSD with central nervous system disease.
最初的ⅢA型黏多糖贮积症（MPS IIIA）小鼠是在一个由四种不同品系构成的混合背景中被鉴定出来的。为确保这种溶酶体贮积病（LSD）模型的长期稳定性和基因同质性，本研究的目的是培育并鉴定一个C57BL/6同源近交系。B6.Cg-Sgsh(mps3a)品系与最初的混合供体品系相比具有优势，出生时即表现出低肝脏硫酸酯酶活性以及显著的脑硫酸乙酰肝素衍生二糖升高。出生后脑二糖水平迅速升高，在13周龄时达到平稳状态，是年龄匹配的未受影响小鼠脑内水平的110倍。在大脑皮质和小脑神经元以及肝脏肝细胞和库普弗细胞中观察到典型的溶酶体包涵体。在脑中还检测到泛素阳性球体和GM(2)-神经节苷脂。在雄性小鼠中使用莫里斯水迷宫实验，20周龄的B6.Cg-Sgsh(mps3a) MPS IIIA小鼠明显存在记忆和空间学习障碍。其他行为变化包括运动、认知和感觉缺陷以及攻击性。如先前在最初的混合背景品系中所观察到的那样，雄性B6.Cg-Sgsh(mps3a) MPS IIIA小鼠比雌性表现出更多行为异常。受影响的小鼠通常存活至9至12月龄，之后出于人道原因死亡或实施安乐死。总体而言，新的同源近交系与先前描述的混合MPS IIIA品系之间存在明显的细微差异。近交系的可用性将确保更可重复的实验结果，从而有助于我们实现为患有中枢神经系统疾病的溶酶体贮积病开发有效疗法的目标。
