Heuer Gregory G, Passini Marco A, Jiang Kanli, Parente Michael K, Lee Virginia M-Y, Trojanowski John Q, Wolfe John H
Department of Pathobiology and Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ann Neurol. 2002 Dec;52(6):762-70. doi: 10.1002/ana.10373.
The mucopolysaccharidoses are caused by inherited deficiencies of lysosomal enzymes involved in the degradative pathway of glycosaminoglycans. Lysosomal storage leads to cellular and organ dysfunction, including mental retardation. Storage lesions are found throughout the diseased brain, but little is known about the cellular and molecular mechanisms that underlie brain dysfunction. In the mouse model of mucopolysaccharidosis VII, we found that specific regions of the brain are vulnerable to neurodegeneration, characterized by the presence of ubiquitin inclusions, neurofilament inclusions, and reactive astrogliosis. The pathological lesions were found predominantly in the hippocampus and cerebral cortex, and they increased progressively with age. Treatment with a recombinant viral vector to correct the enzymatic defect quantitatively reversed the neurodegenerative lesions in targeted regions to normal levels.
黏多糖贮积症是由参与糖胺聚糖降解途径的溶酶体酶遗传性缺乏引起的。溶酶体贮积导致细胞和器官功能障碍，包括智力迟钝。在患病大脑中发现了贮积性病变，但对大脑功能障碍背后的细胞和分子机制知之甚少。在黏多糖贮积症VII型小鼠模型中，我们发现大脑的特定区域易发生神经退行性变，其特征是存在泛素包涵体、神经丝包涵体和反应性星形胶质细胞增生。病理病变主要见于海马体和大脑皮层，且随年龄增长而逐渐增加。用重组病毒载体进行治疗以纠正酶缺陷，可使靶向区域的神经退行性病变定量逆转至正常水平。
