Petkau T L, Hill A, Leavitt B R
Center for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
Center for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Division of Neurology, Department of Medicine, University of British Columbia Hospital, S192, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada; Brain Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Neuroscience. 2016 Feb 19;315:175-95. doi: 10.1016/j.neuroscience.2015.12.006. Epub 2015 Dec 14.
Loss-of-function mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal lobar degeneration (FTLD). A high degree of heterogeneity in the age-of-onset, duration of disease, and clinical presentation of FTLD, even among families carrying the same GRN mutation, suggests that additional modifying genes may be important to pathogenesis. Progranulin-knockout mice display subtle behavioral abnormalities and progressive neuropathological changes, as well as altered dendritic morphology and synaptic deficits in the hippocampus. In this study we evaluated multiple neuropathological endpoints in aged progranulin knockout mice and their wild-type littermates on two different genetic backgrounds: C57Bl/6 and 129/SvImJ. We find that in most brain regions, both strains are susceptible to progranulin-mediated neuropathological phenotypes, including astrogliosis, microgliosis, and highly accelerated deposition of the aging pigment lipofuscin. Neuroinflammation due to progranulin deficiency is exaggerated in the B6 strain and present, but less pronounced, in the 129 strain. Differences between the strains in hippocampal neuron counts and neuronal morphology suggest a complex role for progranulin in the hippocampus. We conclude that core progranulin-mediated neurodegenerative phenotypes are penetrant on multiple inbred mouse strains, but that genetic background modulates progranulin's role in neuroinflammation and hippocampal biology.
前颗粒蛋白基因（GRN）的功能丧失突变是家族性额颞叶痴呆（FTLD）的常见病因。FTLD在发病年龄、病程和临床表现方面存在高度异质性，即使在携带相同GRN突变的家族中也是如此，这表明其他修饰基因可能对发病机制很重要。前颗粒蛋白敲除小鼠表现出细微的行为异常和进行性神经病理变化，以及海马体中树突形态改变和突触缺陷。在本研究中，我们评估了两种不同遗传背景（C57Bl/6和129/SvImJ）下老年前颗粒蛋白敲除小鼠及其野生型同窝小鼠的多个神经病理终点。我们发现，在大多数脑区，两种品系都易患前颗粒蛋白介导的神经病理表型，包括星形胶质细胞增生、小胶质细胞增生以及衰老色素脂褐质的高度加速沉积。前颗粒蛋白缺乏引起的神经炎症在B6品系中更为严重，在129品系中也存在，但不太明显。品系之间在海马神经元数量和神经元形态上的差异表明前颗粒蛋白在海马体中起复杂作用。我们得出结论，核心前颗粒蛋白介导的神经退行性表型在多个近交小鼠品系中都有体现，但遗传背景会调节前颗粒蛋白在神经炎症和海马生物学中的作用。
