Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
Institute of Biochemistry and Cell Biology, CNR, Monterotondo Scalo, Rome, Italy.
Nat Commun. 2021 Jun 9;12(1):3495. doi: 10.1038/s41467-021-23903-5.
Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.
溶酶体贮积症的特征是肝素硫酸代谢改变，包括黏多糖贮积症 (MPS) III 和 MPS-II，表现为溶酶体功能障碍，导致儿童神经退行性变和痴呆。在溶酶体贮积症中，痴呆发生在严重且对抗疗法有抗性的、原因不明的自闭症样症状之前。使用 MPS-IIIA 的小鼠和细胞模型，我们发现自闭症样行为是由于中脑多巴胺神经元在胚胎发生期间过度增殖引起的，这不是由于溶酶体功能障碍，而是由于 HS 功能改变。多巴胺 D1 样受体拮抗剂 SCH-23390 可纠正过度多巴胺能和自闭症样行为，为 D2 样拮抗剂氟哌啶醇提供了一种潜在的替代策略，氟哌啶醇在 MPS-IIIA 中仅有最小的治疗效果。这些发现确定了由于 HS 功能改变导致的胚胎多巴胺能神经发育缺陷，导致 MPS-II 和 MPS-IIIA 中的自闭症样行为，并支持了改变的 HS 相关基因功能是自闭症病因的证据。
