Lysosomal dysfunction may be an important factor in the pathogenesis of neurodegenerative disorders such as Parkinson's disease (PD). Heterozygous mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) have been found in PD patients, and some but not all mutations in other lysosomal enzyme genes, for example, NPC1 and MCOLN1 have been associated with PD. We have examined the behaviour and brain structure of mice carrying a D31N mutation in the sulphamidase (Sgsh) gene which encodes a lysosomal sulphatase. Female heterozygotes and wildtype mice aged 12‐, 15‐, 18‐ and 21‐months of age underwent motor phenotyping and the brain was comprehensively evaluated for disease‐associated lesions. Heterozygous mice exhibited impaired performance in the negative geotaxis test when compared with wildtype mice. Whilst the brain of Sgsh heterozygotes aged up to 21‐months did not exhibit any of the gross features of PD, Alzheimer's disease or the neurodegenerative lysosomal storage disorders, for example, loss of striatal dopamine, reduced GBA activity, α‐synuclein‐positive inclusions, perturbation of lipid synthesis, or cerebellar Purkinje cell drop‐out, we noted discrete structural aberrations in the dendritic tree of cortical pyramidal neurons in 21‐month old animals. The overt disease lesions and resultant phenotypic changes previously described in individuals with heterozygous mutations in lysosomal enzyme genes such as glucocerebrosidase may be enzyme dependent. By better understanding why deficiency in, or mutant forms of some but not all lysosomal proteins leads to heightened risk or earlier onset of classical neurodegenerative disorders, novel disease‐causing mechanisms may be identified.

中文翻译：

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SGSH 杂合性是早发性神经退行性疾病的危险因素吗？

溶酶体功能障碍可能是帕金森病 (PD) 等神经退行性疾病发病机制的重要因素。在 PD 患者中发现了编码溶酶体酶葡糖脑苷脂酶 ( GBA1 )的基因的杂合突变，并且其他溶酶体酶基因的一些但不是全部突变，例如NPC1和MCOLN1与 PD 相关。我们研究了在磺胺酶 ( Sgsh) 中携带 D31N 突变的小鼠的行为和大脑结构。) 编码溶酶体硫酸酯酶的基因。对 12、15、18 和 21 个月大的雌性杂合子和野生型小鼠进行运动表型分析，并全面评估大脑的疾病相关病变。与野生型小鼠相比，杂合小鼠在负趋地性测试中表现出受损的表现。虽然Sgsh的大脑长达 21 个月的杂合子没有表现出任何 PD、阿尔茨海默病或神经退行性溶酶体贮积症的总体特征，例如纹状体多巴胺的丧失、GBA 活性降低、α-突触核蛋白阳性内含物、脂质合成紊乱，或小脑浦肯野细胞脱落，我们注意到 21 个月大的动物皮质锥体神经元树突树中的离散结构畸变。先前在溶酶体酶基因（如葡糖脑苷脂酶）杂合突变的个体中描述的明显疾病病变和由此产生的表型变化可能是酶依赖性的。通过更好地理解为什么某些但不是全部溶酶体蛋白的缺陷或突变形式会导致经典神经退行性疾病的风险增加或提前发作，