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Calpain cleavage of α-synuclein and T-cell reactivity in Parkinson’s disease

Calpain cleavage of α-synuclein and T-cell reactivity in Parkinson’s disease
帕金森病中α-突触核蛋白的钙蛋白酶裂解和 T 细胞反应性
批准号:
10042307
负责人:
NAREN L BANIK
金额:
$41.11万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-05-15 至 2024-04-30

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中文摘要
翻译
摘要 帕金森病(PD)是一种衰弱的进行性退行性运动障碍,与缺乏 黑质(SN)多巴胺能神经元与α-突触核蛋白(α-SYN)的积聚 大脑,小胶质细胞的激活,炎性细胞因子/趋化因子的产生,CD4T细胞的渗透, 和神经退化。最有效的疗法L-多巴并不能阻止疾病的发展,而 其递进性机制尚不清楚。钙蛋白酶是一种受钙调节的半胱氨酸蛋白酶,它发挥着 在帕金森病脊髓变性中的关键作用及其在α-SYN聚集、活化中的作用 小胶质细胞、T细胞及其迁移表明钙蛋白酶在促进炎症过程和 疾病的发展。虽然α-SYN的CalPain-1裂解促进了PD样疾病中的突触核蛋白聚集, 两个主要的Calain亚型,CalPain-1和CalPain-2,在α-SYN表达中的精确参与 CD4T细胞仍不清楚。初步研究发现MPTP小鼠体内存在一种亚型的CD4T细胞, 这一点被Calain抑制剂取消,这表明Calain和CD4T细胞的激活可能在 在帕金森病的炎症过程和疾病进展中的关键作用。初步数据还表明, SiRNA介导的Calain-2基因敲除减少人B细胞的抗原提呈并抑制 CD4T细胞的活化。因此,我们假设不同的钙蛋白亚型的激活可能有利于 帕金森病患者α同源反应性CD4T细胞亚型的扩增。我们还假设CalPain 抑制α-SYN可能减弱炎性T细胞的聚集和扩张,减轻炎症和 支持帕金森病患者的神经元存活和改善预后。提出了两个具体的目标来测试 假设:(目的1)研究calain-1或calain-2的激活是否与小胶质细胞有关 α-SYN递呈给CD4T细胞导致帕金森病样疾病进展和神经变性 小鼠的疾病。(目的2)确定抑制Calain-2是否会减少α-SYN的小胶质细胞提呈 并产生致病的CD4T细胞,延缓帕金森病小鼠模型的疾病进展。目标是 本研究的目的是探讨CalPain-1和CalPain-2在α-SYN反应性致病CD_4形成中的作用。 T细胞,以及来自MPTP小鼠的CD4T细胞亚群是否能在 免疫缺陷小鼠。计划进行研究以确定CalPain-1的缺失是否会减弱α-SYN 利用Calain-1基因敲除(KO)小鼠聚集和扩增CD4T细胞。此外,还包括 Calain-2抑制剂将在炎性CD4T细胞反应和炎症反应的改变研究中进行评估 Calain-1 KO小鼠细胞因子/趋化因子的产生测试不同的钙蛋白亚型在体内的作用 α-SYN反应性致病T细胞的产生和诱导神经元的死亡和变性可能导致 开发一种治疗帕金森病和其他神经退行性疾病的新方法。
英文摘要
Summary Parkinson's disease (PD) is a debilitating progressive degenerative movement disorder associated with loss of dopaminergic (DA) neurons in the substantia nigra (SN) along with the accumulation of α-synuclein (α-syn) in the brain, activation of microglia, production of inflammatory cytokines/chemokines, infiltration of CD4+ T-cells, and neurodegeneration. The most potent therapy, L-dopa, does not block disease progression, and the mechanism of the progressive nature is unclear. Calpain, a cysteine protease regulated by calcium, plays a pivotal role in SN and SC (spinal cord) degeneration in PD, and its role in α-syn aggregation, activation of microglia, T cells and their migration indicate calpain to be crucial in promoting the inflammatory process and disease progression. While calpain-1 cleavage of α-syn promotes synuclein aggregation in PD-like diseases, the precise involvement of the two major calpain isoforms, calpain-1 and calpain-2, in α-syn presentation to CD4+ T-cells remains unknown. Preliminary studies here identified a subtype of CD4+ T cells in MPTP mice, which was abolished by calpain inhibitor, suggesting that activation of calpain and CD4+ T cells may play critical roles in the inflammatory process and disease progression in PD. Preliminary data also suggest that siRNA-mediated knockdown of calpain-2 diminishes antigen presentation by human B-cells and inhibits activation of CD4+ T cells. Thus, we hypothesize that activation of distinct calpain isoforms may favor expansion of a subtype of α-syn-reactive CD4+ T cells in PD-like disease. We also hypothesize that calpain inhibition may attenuate α-syn aggregation and expansion of inflammatory T cells, reduce inflammation and support neuronal survival and improved outcome in PD patients. Two specific aims are proposed to test the hypothesis: (Aim 1) To investigate whether activation of calpain-1 or calpain-2 is linked with microglial presentation of α-syn to CD4+ T cells resulting in disease progression and neurodegeneration in PD-like disease in mice. (Aim 2) To determine whether inhibition of calpain-2 reduces microglial presentation of α-syn and generation of pathogenic CD4+ T cells, attenuating disease progression in mouse models of PD. The goal of this study is to investigate the role of calpain-1 and calpain-2 in generating α-syn-reactive pathogenic CD4+ T cells, and whether a subpopulation of CD4+ T cells from MPTP mice can induce PD-like disease in immunodeficient mice. Studies are planned to determine whether deletion of calpain-1 attenuates α-syn aggregation and expansion of CD4+ T cells using calpain-1 knockout (KO) mice. In addition, the role of calpain-2 inhibitor will be assessed in the study of alteration of inflammatory CD4+ T cell response and production of cytokines/chemokines in calpain-1 KO mice. Testing the effects of distinct calpain isoforms in the generation of α-syn-reactive pathogenic T cells and induction neuronal death and degeneration may lead to development of a novel approach for treating PD as well as other neurodegenerative disorders.
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Research Career Scientist for Naren Banik, PhD
Research Career Scientist for Naren Banik, PhD
Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease
Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease
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