A central role for calcineurin in protein misfolding neurodegenerative diseases
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- 作者：Syed Zahid Ali Shah ; Tariq Hussain ; Deming Zhao…
- 关键词：Calcineurin regulation ; Microglial activation ; Tacrolimus ; Neuroinflammation ; Phosphorylated cAMP response element ; binding protein (pCREB) and phosphorylated Bcl2 ; associated death promoter (pBAD)
- 刊名：Cellular and Molecular Life Sciences
- 出版年：2017
- 出版时间：March 2017
- 年：2017
- 卷：74
- 期：6
- 页码：1061-1074
- 全文大小：
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Cell Biology; Biomedicine, general; Life Sciences, general; Biochemistry, general;
- 出版者：Springer International Publishing
- ISSN：1420-9071
- 卷排序：74
文摘
Accumulation of misfolded/unfolded aggregated proteins in the brain is a hallmark of many neurodegenerative diseases affecting humans and animals. Dysregulation of calcium (Ca2+) and disruption of fast axonal transport (FAT) are early pathological events that lead to loss of synaptic integrity and axonal degeneration in early stages of neurodegenerative diseases. Dysregulated Ca2+ in the brain is triggered by accumulation of misfolded/unfolded aggregated proteins in the endoplasmic reticulum (ER), a major Ca2+ storing organelle, ultimately leading to neuronal dysfunction and apoptosis. Calcineurin (CaN), a Ca2+/calmodulin-dependent serine/threonine phosphatase, has been implicated in T cells activation through the induction of nuclear factor of activated T cells (NFAT). In addition to the involvement of several other signaling cascades, CaN has been shown to play a role in early synaptic dysfunction and neuronal death. Therefore, inhibiting hyperactivated CaN in early stages of disease might be a promising therapeutic strategy for treating patients with protein misfolding diseases. In this review, we briefly summarize the structure of CaN, inhibition mechanisms by which immunosuppressants inhibit CaN, role of CaN in maintaining neuronal and synaptic integrity and homeostasis and the role played by CaN in protein unfolding/misfolding neurodegenerative diseases.