Akerud P, Holm P C, Castelo-Branco G, Sousa K, Rodriguez F J, Arenas E
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, 17177 Stockholm, Sweden.
Mol Cell Neurosci. 2002 Oct;21(2):205-22. doi: 10.1006/mcne.2002.1171.
Persephin (PSP) is a neurotrophic factor of the GDNF family that has been found to promote the survival of multiple populations of neurons. In the present study we have examined: (1) the mechanism of action and the function of PSP on nigrostriatal dopamine neurons and (2) the therapeutic potential of PSP, delivered by neural stem cells (NSCs) in a model of Parkinson's disease. Interestingly we found that the prenatal ventral mesencephalon and the newborn striatum express high levels of PSP mRNA. Moreover, midbrain dopamine neurons express its preferred receptor GFRalpha4, allowing a cis type of action of PSP on dopamine neurons. Primary culture studies showed that PSP is as potent and efficacious as GDNF at promoting both survival and neuritogenesis of midbrain dopamine neurons. To study the function and therapeutic potential of PSP in vivo we engineered NSCs to overexpress PSP. PSP-c17.2 cells were found to stably express PSP mRNA and protein for at least 3 months in vivo, to disperse within the striatum, and to give rise to neurons, astrocytes, and a large proportion of oligodendrocytes that integrated within white matter tracts in the striatum. Moreover, PSP-c17.2 cells enhanced dopamine-dependent behavioral parameters in unlesioned mice and prevented the loss of dopamine neurons and the behavioral impairment of mice receiving intrastriatal 6-OHDA injections. Thus, our findings are consistent with a direct action of PSP on developing and adult midbrain dopamine neurons and suggest that the delivery of PSP by NSCs may constitute a very useful strategy in the treatment of Parkinson's disease.
Persephin（PSP）是胶质细胞源性神经营养因子（GDNF）家族的一种神经营养因子，已被发现可促进多种神经元群体的存活。在本研究中，我们研究了：（1）PSP对黑质纹状体多巴胺能神经元的作用机制和功能；（2）在帕金森病模型中，神经干细胞（NSC）递送PSP的治疗潜力。有趣的是，我们发现产前腹侧中脑和新生纹状体表达高水平的PSP mRNA。此外，中脑多巴胺能神经元表达其优先受体GFRalpha4，使得PSP对多巴胺能神经元具有顺式作用类型。原代培养研究表明，在促进中脑多巴胺能神经元的存活和神经突生成方面，PSP与GDNF一样有效。为了研究PSP在体内的功能和治疗潜力，我们对NSC进行基因工程改造使其过表达PSP。发现PSP - c17.2细胞在体内至少3个月稳定表达PSP mRNA和蛋白，在纹状体内分散，并产生整合到纹状体白质束中的神经元、星形胶质细胞和很大比例的少突胶质细胞。此外，PSP - c17.2细胞增强了未受损小鼠中多巴胺依赖的行为参数，并防止了接受纹状体内6 - 羟基多巴胺注射的小鼠多巴胺能神经元的丢失和行为障碍。因此，我们的研究结果与PSP对发育中和成年中脑多巴胺能神经元的直接作用一致，并表明NSC递送PSP可能构成治疗帕金森病的一种非常有用的策略。
