Role of Prokineticin 2 in Metal Neurotoxicity

摘要 慢性环境暴露于神经毒性浓度的锰会影响基底节 并与帕金森氏症的病因学联系在一起。在基底节(BG)内，Mn主要积聚 并导致GABA能神经元功能障碍，导致 BG神经电路。与帕金森氏病(PD)不同的是，黑质中的DAR能核受锰的影响不大 神经毒性。尽管锰的神经毒性表现为锥体外系运动损伤，但动物和人类 神经毒性研究表明，它还与各种神经精神和认知障碍有关。 多条证据表明人类在职业和环境中均存在嗅觉缺陷。 曝光。尽管有证据表明嗅觉障碍与锰神经毒性的BG病理有关，但潜在的 神经毒理学机制仍然知之甚少。最近，我们报道了神经肽 原激动素2(PK2)在神经毒素诱导的DAR能神经毒性早期迅速上调 帕金森氏症的动物模型，它参与了一种新的代偿性保护性反应 通过激活促进生存的通路而导致的神经退化。我们还获得了令人兴奋的新数据，显示出类似的 体外锰诱导的神经毒性及黑质和嗅球中PK2的双相表达 (OB)染锰动物的脑区，而不是纹状体。此外，我们的初步研究出人意料地 研究发现，对PK2受体或重组PK2(RPK2)的药理刺激显著上调 胶质源性神经营养因子在体内外星形胶质细胞中的表达和释放。 其他初步结果显示，PK2和GDNF在OB中有很强的共存。因此，我们假设 BG中PK2-GDNF信号诱导模式的差异导致了BG的不同脆弱性 GABA能和DAR能神经元对锰的神经毒性。此外，锰还引起PK2-GDNF信号的损伤 影响OB功能和纹状体神经元存活所需的神经发生。要充分确立 在锰诱导的神经毒性损伤过程中，BG和嗅觉区的PK2-GDNF轴，我们将系统地 追求以下特定目标：(I)映射BG、OB、室下区(SVZ)中PK2的差异表达， 和吻侧迁移流(RMS)区域，并在功能上与神经发生、脑区域特异性相关 慢性锰神经毒性小鼠模型的神经元脆弱性和神经行为缺陷；(Ii)确定 PK2是否调节GDNF水平及PK2信号调控的分子机制 GDNF在细胞和动物模型中的锰神经毒性；以及(Iii)评价翻译神经保护效果 新的PK2受体激动剂和AAV-PK2/GDNF基因治疗在锰神经毒性动物模型中的应用。总的来说， 我们预测，我们提出的研究将为金属诱导的血糖和嗅觉提供新的机制见解。 功能障碍及其在环境相关帕金森综合征发病机制中的作用 治疗策略。

Abstract Chronic environmental exposure to neurotoxic concentrations of manganese (Mn) affects the basal ganglia system and has been linked to the etiology of Parkinsonism. Within basal ganglia (BG), Mn primarily accumulates in the globus pallidus and causes neuronal dysfunction in GABAergic neurons, resulting in dysregulation of the BG neural circuitry. Unlike Parkinson’s disease (PD), DAergic nuclei in the SN are not greatly affected by Mn neurotoxicity. Although Mn neurotoxicity manifests as extrapyramidal motor impairments, animal and human neurotoxicity studies indicate that it is also associated with various neuropsychiatric and cognitive disabilities. Several lines of evidence reveal olfactory deficits in humans following both occupational and environmental Mn exposure. Despite evidence linking olfactory dysfunction and BG pathology in Mn neurotoxicity, the underlying neurotoxicological mechanisms remain poorly understood. Recently, we reported that the neuropeptide prokineticin 2 (PK2) is rapidly upregulated in the early stages of DAergic neurotoxicity in a neurotoxin-induced animal model of Parkinsonism, and it participates in a novel compensatory protective response to counteract neurodegeneration by activating pro-survival pathways. We also obtained exciting new data showing a similar biphasic expression pattern for PK2 during Mn-induced neurotoxicity in vitro and in the SN and olfactory bulb (OB) regions, but not the striatum, of Mn-treated animals. Furthermore, our preliminary studies surprisingly identified that pharmacological stimulation of PK2 receptors or recombinant PK2 (rPK2) significantly upregulates the glial-derived neurotrophic factor (GDNF) expression and release in astrocytes both in vitro and in vivo. Additional preliminary results revealed a robust colocalization of PK2 and GDNF in OB. Thus, we hypothesize that disparity in the induction pattern of PK2-GDNF signaling in BG contributes to the differential vulnerability of GABAergic and DAergic neurons to Mn neurotoxicity. Also, Mn-induced impairment in PK2-GDNF signaling affects neurogenesis required for OB function and striatal neuronal survival. To fully establish the role of the PK2-GDNF axis in the BG and olfactory regions during Mn-induced neurotoxic insult, we will systematically pursue the following specific aims: (i) Map differential PK2 expression in BG, OB, subventricular zone (SVZ), and rostral migratory stream (RMS) regions and functionally correlate with neurogenesis, brain region-specific neuronal vulnerability and neurobehavioral deficits in mouse models of chronic Mn neurotoxicity; (ii) determine whether PK2 regulates GDNF levels and characterize the molecular mechanism of PK2 signaling in regulating GDNF in cell and animal models of Mn neurotoxicity; and (iii) evaluate the translational neuroprotective efficacy of novel PK2 receptor agonism and AAV-PK2/GDNF gene therapy in animal models of Mn neurotoxicity. Overall, we predict that our proposed studies will provide novel mechanistic insights into metal-induced BG and olfactory dysfunction and its role in the pathogenesis of environmentally linked Parkinsonism and will offer a novel therapeutic strategy.