Role of Prokineticin 2 in Metal Neurotoxicity

Prokineticin 2 在金属神经毒性中的作用

• 批准号: 10587599
• 负责人: ARTHI KANTHASAMY
• 金额: $ 33.98万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-25 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587599
• 关键词: Adult; Affect; Agonist; Animal Model; Animals; Anosmia; Astrocytes; Basal Ganglia; Brain region; C57BL/6 Mouse; Cell Nucleus; Cell model; Cells; Chemotactic Factors; Chronic; Corpus striatum structure; Data; Dendroaspis; Disparity; Dose; Environment; Environmental Exposure; Etiology; Exposure to; Functional disorder; Gene Expression; Globus Pallidus; Goals; Health; Heavy Metals; Homologous Gene; Human; Idiopathic Parkinson Disease; Impairment; In Vitro; Industrialization; Kallmann Syndrome; Link; Manganese; Maps; Mediating; Metal exposure; Metals; Modeling; Molecular; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Deficit; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Neuropeptides; Neurotoxins; Occupational; Olfactory dysfunction; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathology; Pathway interactions; Pattern; Peptides; Phase; Predisposition; Prosencephalon; Recombinants; Reporting; Role; Signal Pathway; Signal Transduction; Source; Stream; Stress; System; Therapeutic; Time; Up-Regulation; Venoms; astrocyte progenitor; cognitive disability; gene therapy; human tissue; in vivo; insight; migration; motor deficit; motor impairment; mouse model; nerve stem cell; neural circuit; neurobehavioral; neurogenesis; neuron loss; neuronal survival; neuroprotection; neuropsychiatry; neurotoxic; neurotoxicity; neurotoxicology; neurotrophic factor; novel; novel therapeutic intervention; olfactory bulb; pharmacologic; protective effect; receptor; receptor expression; release factor; response; subventricular zone; translational approach

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.

摘要 慢性环境暴露于神经毒性浓度的锰（Mn）影响基底神经节 系统，并已被链接到帕金森氏症的病因。在基底神经节（BG）内，Mn主要积聚 并引起GABA能神经元的神经元功能障碍，从而导致 BG神经回路。与帕金森病（PD）不同，SN中的DA能核不受Mn的影响 神经毒性虽然锰的神经毒性表现为锥体外系运动障碍，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残疾有关。 一些证据表明，在职业和环境锰中毒后，人类的嗅觉缺陷 exposure.尽管有证据表明嗅觉功能障碍和BG病理学在锰神经毒性中存在联系， 神经毒理学机制仍然知之甚少。最近，我们报道了神经肽 在神经毒素诱导的DA能神经毒性的早期阶段，前动力蛋白2（PK 2）迅速上调。 帕金森症的动物模型，它参与了一种新的补偿性保护反应，以抵消 通过激活促生存途径来抑制神经退行性变。我们还获得了令人兴奋的新数据， 在锰诱导的神经毒性中PK 2的双相表达模式在体外和SN和嗅球中 (OB)区域，但不是纹状体，锰处理的动物。此外，我们的初步研究令人惊讶地 确定PK 2受体或重组PK 2（rPK 2）的药理学刺激显著上调 胶质源性神经营养因子（GDNF）在体内外星形胶质细胞中的表达和释放。 另外的初步结果揭示了PK 2和GDNF在OB中的稳健共定位。因此，我们假设 BG中PK 2-GDNF信号传导诱导模式的差异导致了 GABA能和DA能神经元对Mn神经毒性的反应。此外，锰诱导的PK 2-GDNF信号转导障碍 影响OB功能和纹状体神经元存活所需的神经发生。为了充分发挥 在锰诱导的神经毒性损伤过程中，BG和嗅觉区域的PK 2-GDNF轴，我们将系统地 追求以下具体目标：（i）绘制BG、OB、脑室下区（SVZ）中的差异PK 2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 慢性锰神经毒性小鼠模型中的神经元脆弱性和神经行为缺陷;（ii）确定 PK 2是否调节GDNF水平，并表征PK 2信号转导在调节GDNF水平中的分子机制。 GDNF在Mn神经毒性的细胞和动物模型中的作用;和（iii）评估翻译的神经保护功效 新型PK 2受体激动剂和AAV-PK 2/GDNF基因治疗在Mn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BG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病发病机制中的作用，并将提供一种新的 治疗策略