HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch-Nyhan disease.
HGprt deficiency disrupts dopaminergic circuit development in a genetic mouse model of Lesch-Nyhan disease.
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DOI：
10.1007/s00018-022-04326-x
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发表时间：
2022-06-04
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--
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在Lesch-Nyhan病（LND）中，嘌呤补救酶次黄嘌呤鸟嘌呤磷酸核糖转移酶（HGprt）的缺乏导致以肌张力障碍、认知缺陷和失能自伤行为为主的特征性神经行为表型。几十年来，人们已经知道LND与中脑多巴胺神经元功能障碍有关，而没有明显的脑结构异常。新兴的尸检和体外证据支持LND中多巴胺能功能障碍是发育起源的假设，但具体的致病机制尚未被揭示。在目前的研究中，HGprt缺乏导致胚胎发育期间小鼠的特定神经发育异常，特别是影响发育中的中脑多巴胺（mDA）神经元的增殖和迁移。在E14.5的突变胚胎中，增殖增加，伴随着细胞周期退出减少，分裂细胞的分布和方向表明过早偏离其迁移路线。一个结构异常的放射状胶质样支架支持这种mDA神经元迁移可能是这些异常的基础。因此，这些异常与TH+细胞所占面积的增加和E18.5时异常mDA亚群组织相关。最后，多巴胺能神经支配紊乱的前额和减少HGPRT缺乏初级运动和躯体感觉皮层。这些数据提供了直接的体内证据，在LND的大脑疾病的神经发育的性质。未来的研究不仅应该关注报告的神经发育异常的具体分子机制，而且还应该关注治疗干预的最佳时机，以挽救DA神经元缺陷，这也可能与其他神经发育障碍有关。在线版本包含补充材料，可通过10.1007/s 00018 -022-04326-x获得。
In Lesch–Nyhan disease (LND), deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase (HGprt) leads to a characteristic neurobehavioral phenotype dominated by dystonia, cognitive deficits and incapacitating self-injurious behavior. It has been known for decades that LND is associated with dysfunction of midbrain dopamine neurons, without overt structural brain abnormalities. Emerging post mortem and in vitro evidence supports the hypothesis that the dopaminergic dysfunction in LND is of developmental origin, but specific pathogenic mechanisms have not been revealed. In the current study, HGprt deficiency causes specific neurodevelopmental abnormalities in mice during embryogenesis, particularly affecting proliferation and migration of developing midbrain dopamine (mDA) neurons. In mutant embryos at E14.5, proliferation was increased, accompanied by a decrease in cell cycle exit and the distribution and orientation of dividing cells suggested a premature deviation from their migratory route. An abnormally structured radial glia-like scaffold supporting this mDA neuronal migration might lie at the basis of these abnormalities. Consequently, these abnormalities were associated with an increase in area occupied by TH+ cells and an abnormal mDA subpopulation organization at E18.5. Finally, dopaminergic innervation was disorganized in prefrontal and decreased in HGprt deficient primary motor and somatosensory cortices. These data provide direct in vivo evidence for a neurodevelopmental nature of the brain disorder in LND. Future studies should not only focus the specific molecular mechanisms underlying the reported neurodevelopmental abnormalities, but also on optimal timing of therapeutic interventions to rescue the DA neuron defects, which may also be relevant for other neurodevelopmental disorders. The online version contains supplementary material available at 10.1007/s00018-022-04326-x.
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