Calpain activation and progression of inflammatory cycles in Parkinson's disease.
Calpain activation and progression of inflammatory cycles in Parkinson's disease.
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DOI：
10.31083/j.fbl2701020
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发表时间：
2022-01-13
影响因子：
3.1
通讯作者：
Haque, Azizul
中科院分区：
文献类型：
--
作者：
Gao, Andrew;McCoy, Hannah M.;Zaman, Vandana;Shields, Donald C.;Banik, Naren L.;Haque, Azizul
关键词：
帕金森病 (PD) 是一种进行性中枢神经系统 (CNS) 神经退行性疾病，影响着全球 630 万人，且尚无有效治疗方法。目前的疗法旨在减轻帕金森病的影响并缓解患者的症状。 PD 的发病机制涉及多种途径，导致中枢神经系统中的神经炎症和多巴胺能神经元的破坏。本综述重点关注 PD 病理学以及钙蛋白酶（一种中性蛋白酶）作为各种免疫细胞（如 T 细胞、小胶质细胞和星形胶质细胞）调节剂的作用，这些细胞会导致大脑和脊髓 (SC) 中持续的神经炎症反应和神经元损失。钙蛋白酶在有毒 α-突触核蛋白 (α-syn)（一种突触前神经蛋白）和其他细胞器的裂解和聚集中发挥重要作用，导致线粒体功能障碍和氧化应激。 α-Syn 聚集导致路易体 (LB) 的形成，路易体通过脂质双层渗透、钙离子 (Ca2+) 流入、氧化应激和血脑屏障 (BBB) 损伤进一步导致神经元损伤。功能失调的线粒体会破坏细胞质 Ca2+ 浓度的稳定性，从而提高细胞内 Ca2+；这会导致钙蛋白酶过度激活和持续的炎症反应。 α-Syn 聚集还会通过酪氨酸羟化酶 (TH) 的磷酸化导致多巴胺合成中断，酪氨酸羟化酶 (TH) 是酪氨酸转化为左旋多巴 (L-DOPA) 的关键酶，左旋多巴是多巴胺的氨基酸前体。多巴胺水平降低会导致多巴胺受体 (DR) 信号传导发生改变，最终激活促炎 T 细胞，进一步促进炎症反应。所有这些过程共同导致帕金森病中出现的神经炎症、变性并最终导致神经元死亡。 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP——神经毒素 1-甲基-4-苯基吡啶鎓 (MPP+) 的前药）、鱼藤酮（一种环境神经毒素）和 6-羟基多巴胺（6-OHDA——一种神经毒性合成有机化合物）注射到啮齿动物体内时会诱发 PD 样病症。所有三种药物都通过相似的机制发挥作用，并导致黑质 (SN) 以及最近在脊髓 (SC) 运动神经元中发现的多巴胺能神经元变性。这些神经毒素还会增加钙蛋白酶活性，进一步加剧神经炎症反应。因此，钙蛋白酶抑制剂被认为是 PD 的潜在疗法，不仅可以预防 SN 中的钙蛋白酶相关炎症和神经退行性反应，还可以预防 SC 中的神经退行性反应。
Parkinson’s disease (PD) is a progressive, neurodegenerative condition of the central nervous system (CNS) affecting 6.3 million people worldwide with no curative treatments. Current therapies aim to mitigate PD’s effects and offer symptomatic relief for patients. Multiple pathways are involved in the pathogenesis of PD, leading to neuroinflammation and the destruction of dopaminergic neurons in the CNS. This review focuses on PD pathology and the role of calpain, a neutral protease, as a regulator of various immune cells such as T-cells, microglia and astrocytes which lead to persistent neuroinflammatory responses and neuronal loss in both the brain and spinal cord (SC). Calpain plays a significant role in the cleavage and aggregation of toxic α-synuclein (α-syn), a presynaptic neural protein, and other organelles, contributing to mitochondrial dysfunction and oxidative stress. α-Syn aggregation results in the formation of Lewy bodies (LB) that further contribute to neuronal damage through lipid bilayer penetration, calcium ion (Ca2+) influx, oxidative stress and damage to the blood brain barrier (BBB). Dysfunctional mitochondria destabilize cytosolic Ca2+ concentrations, raising intracellular Ca2+; this leads to excessive calpain activation and persistent inflammatory responses. α-Syn aggregation also results in the disruption of dopamine synthesis through phosphorylation of tyrosine hydroxylase (TH), a key enzyme involved in the conversion of tyrosine to levodopa (L-DOPA), the amino acid precursor to dopamine. Decreased dopamine levels result in altered dopamine receptor (DR) signaling, ultimately activating pro-inflammatory T-cells to further contribute to the inflammatory response. All of these processes, together, result in neuroinflammation, degeneration and ultimately neuronal death seen in PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP—a prodrug to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+)), rotenone (an environmental neurotoxin), and 6-hydroxydopamine (6-OHDA - a neurotoxic synthetic organic compound) induce PD-like conditions when injected into rodents. All three agents work through similar mechanisms and lead to degeneration of dopaminergic neurons in the substantia nigra (SN) and more recently discovered in motor neurons of the spinal cord (SC). These neurotoxins also increase calpain activity, furthering the neuroinflammatory response. Hence, calpain inhibitors have been posited as potential therapeutics for PD to prevent calpain-related inflammation and neurodegenerative responses in not only the SN but the SC as well.
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DOI：
10.3233/jpd-202417
发表时间：
2021
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Contaldi E;Magistrelli L;Milner AV;Cosentino M;Marino F;Comi C
通讯作者：
Comi C
影响因子：
12.7
作者：
Harms AS;Ferreira SA;Romero-Ramos M
通讯作者：
Romero-Ramos M
影响因子：
12.7
作者：
Bliederhaeuser, Corinna;Grozdanov, Veselin;Danzer, Karin M.
通讯作者：
Danzer, Karin M.
影响因子：
15.9
作者：
Brochard, Vanessa;Combadiere, Behazine;Hunot, Stephane
通讯作者：
Hunot, Stephane
影响因子：
7.8
作者：
Chi, Ying;Fan, Yi;Hu, Gang
通讯作者：
Hu, Gang