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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
总结 帕金森氏病(PD)是一种使人衰弱的进行性退行性运动障碍, 黑质(SN)多巴胺(DA)能神经元沿着α-突触核蛋白(α-syn)的蓄积, 脑,小胶质细胞的活化,炎性细胞因子/趋化因子的产生,CD 4 + T细胞的浸润, 和神经退化最有效的治疗,左旋多巴,不能阻止疾病的进展, 渐进性的机制尚不清楚。钙蛋白酶是一种受钙调节的半胱氨酸蛋白酶, 在PD的SN和SC(脊髓)变性中的关键作用,以及其在α-syn聚集、 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中至关重要, 疾病进展。虽然钙蛋白酶-1切割α-syn促进PD样疾病中的突触核蛋白聚集, 两种主要的钙蛋白酶亚型,钙蛋白酶-1和钙蛋白酶-2,在α-syn呈递中的精确参与, CD 4 + T细胞仍然未知。初步研究在MPTP小鼠中鉴定了一种CD 4 + T细胞亚型, 钙蛋白酶抑制剂可消除这种抑制作用,这表明钙蛋白酶和CD 4 + T细胞的激活可能起作用。 在PD的炎症过程和疾病进展中起关键作用。初步数据还表明, siRNA介导的钙蛋白酶-2敲低减少人B细胞的抗原呈递并抑制 活化CD 4 + T细胞。因此,我们假设不同的钙蛋白酶亚型的激活可能有利于 PD样疾病中α-syn-reactive CD 4 + T细胞亚型的扩增我们还假设钙蛋白酶 抑制可以减弱α-syn聚集和炎性T细胞的扩增,减少炎症, 支持PD患者的神经元存活和改善的结果。提出了两个具体目标,以测试 假设:(目的1)研究calpain-1或calpain-2的激活是否与小胶质细胞 α-syn向CD 4 + T细胞呈递导致PD样疾病进展和神经退行性变 老鼠的疾病(Aim 2)确定抑制钙蛋白酶-2是否减少α-syn的小胶质细胞呈递 和致病性CD 4 + T细胞的产生,减弱PD小鼠模型中的疾病进展。目标 本研究的目的是探讨钙蛋白酶-1和钙蛋白酶-2在产生α-syn-reactive致病性CD 4+中的作用。 T细胞,以及来自MPTP小鼠的CD 4 + T细胞亚群是否可以诱导PD样疾病。 免疫缺陷小鼠研究计划确定是否删除钙蛋白酶-1减弱α-syn 使用钙蛋白酶-1敲除(KO)小鼠的CD 4 + T细胞的聚集和扩增。此外, 钙蛋白酶-2抑制剂将在炎性CD 4 + T细胞应答改变的研究中进行评估, 在钙蛋白酶-1 KO小鼠中细胞因子/趋化因子的产生。测试不同的钙蛋白酶同种型在细胞中的作用, α-syn-reactive致病性T细胞的产生和诱导神经元死亡和变性可能导致 开发用于治疗PD以及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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