Department of Natural Sciences, College of Arts, Sciences, and Letters, University of Michigan-Dearborn, 4901 Evergreen Rd, Dearborn, MI 48128, USA.
Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan-Ann Arbor, 1011 N University Ave, Ann Arbor, MI 48109, USA.
Neuroscience. 2024 Nov 12;560:357-370. doi: 10.1016/j.neuroscience.2024.10.005. Epub 2024 Oct 4.
Loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene can result in hypophosphatasia (HPP), an inherited multi-systemic metabolic disorder that is well-known for skeletal and dental hypomineralization. However, emerging evidence shows that both adult and pediatric patients with HPP suffer from cognitive deficits, higher measures of depression and anxiety, and impaired sensorimotor skills. The cerebellum plays an important role in sensorimotor coordination, cognition, and emotion. To date, the impact of TNAP mutation on the cerebellar circuitry development and function remains poorly understood. The main objective of this study was to investigate the roles of TNAP in cerebellar development and function, with a particular focus on Purkinje cells, in a mouse model of infantile HPP. Male and female wild type (WT) and TNAP knockout (KO) mice underwent behavioral testing on postnatal day 13-14 and were euthanized after completion of behavioral tests. Cerebellar tissues were harvested for gene expression and immunohistochemistry analyses. We found that TNAP mutation resulted in significantly reduced body weight, shorter body length, and impaired sensorimotor functions in both male and female KO mice. These developmental and behavioral deficits were accompanied by abnormal Purkinje cell morphology and dysregulation of genes that regulates synaptic transmission, cellular growth, proliferation, and death. In conclusion, inactivation of TNAP via gene deletion causes developmental delays, sensorimotor impairment, and Purkinje cell maldevelopment. These results shed light on a new perspective of cerebellar dysfunction in HPP.
组织非特异性碱性磷酸酶（TNAP）基因的功能丧失突变可导致低磷酸血症（HPP），这是一种遗传性多系统代谢紊乱疾病，其特征为骨骼和牙齿矿化不全。然而，新出现的证据表明，HPP 的成年和儿科患者均存在认知缺陷、更高程度的抑郁和焦虑以及感觉运动技能受损。小脑在感觉运动协调、认知和情绪中发挥重要作用。迄今为止，TNAP 突变对小脑回路发育和功能的影响仍知之甚少。本研究的主要目的是研究 TNAP 在小脑发育和功能中的作用，特别是在婴儿型 HPP 的小鼠模型中研究 Purkinje 细胞。雄性和雌性野生型（WT）和 TNAP 敲除（KO）小鼠在出生后第 13-14 天进行行为测试，并在完成行为测试后安乐死。收集小脑组织进行基因表达和免疫组织化学分析。我们发现，TNAP 突变导致雄性和雌性 KO 小鼠的体重显著减轻、体长缩短和感觉运动功能受损。这些发育和行为缺陷伴随着 Purkinje 细胞形态异常和调节突触传递、细胞生长、增殖和死亡的基因失调。总之，通过基因缺失使 TNAP 失活会导致发育迟缓、感觉运动障碍和 Purkinje 细胞发育不良。这些结果揭示了 HPP 中小脑功能障碍的新视角。
