Regulatory role of calpain in neuronal death

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Abstract

Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly (ADP-ribose) polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases.

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Autophagy and apoptosis dysfunction in neurodegenerative disorders.

Saeid Ghavami, Shahla Shojaei, Behzad Yeganeh … (2014)

Autophagy and apoptosis are basic physiologic processes contributing to the maintenance of cellular homeostasis. Autophagy encompasses pathways that target long-lived cytosolic proteins and damaged organelles. It involves a sequential set of events including double membrane formation, elongation, vesicle maturation and finally delivery of the targeted materials to the lysosome. Apoptotic cell death is best described through its morphology. It is characterized by cell rounding, membrane blebbing, cytoskeletal collapse, cytoplasmic condensation, and fragmentation, nuclear pyknosis, chromatin condensation/fragmentation, and formation of membrane-enveloped apoptotic bodies, that are rapidly phagocytosed by macrophages or neighboring cells. Neurodegenerative disorders are becoming increasingly prevalent, especially in the Western societies, with larger percentage of members living to an older age. They have to be seen not only as a health problem, but since they are care-intensive, they also carry a significant economic burden. Deregulation of autophagy plays a pivotal role in the etiology and/or progress of many of these diseases. Herein, we briefly review the latest findings that indicate the involvement of autophagy in neurodegenerative diseases. We provide a brief introduction to autophagy and apoptosis pathways focusing on the role of mitochondria and lysosomes. We then briefly highlight pathophysiology of common neurodegenerative disorders like Alzheimer's diseases, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Then, we describe functions of autophagy and apoptosis in brain homeostasis, especially in the context of the aforementioned disorders. Finally, we discuss different ways that autophagy and apoptosis modulation may be employed for therapeutic intervention during the maintenance of neurodegenerative disorders. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Novel targets for Huntington's disease in an mTOR-independent autophagy pathway.

Andrea Williams, Sovan Sarkar, Paul Cuddon … (2008)

Autophagy is a major clearance route for intracellular aggregate-prone proteins causing diseases such as Huntington's disease. Autophagy induction with the mTOR inhibitor rapamycin accelerates clearance of these toxic substrates. As rapamycin has nontrivial side effects, we screened FDA-approved drugs to identify new autophagy-inducing pathways. We found that L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the G(i) signaling activator clonidine induce autophagy. These drugs revealed a cyclical mTOR-independent pathway regulating autophagy, in which cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating G(s)alpha, which regulates cAMP levels. This pathway has numerous potential points where autophagy can be induced, and we provide proof of principle for therapeutic relevance in Huntington's disease using mammalian cell, fly and zebrafish models. Our data also suggest that insults that elevate intracytosolic Ca2+ (like excitotoxicity) inhibit autophagy, thus retarding clearance of aggregate-prone proteins.

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Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis.

Feifan Zhou, Ying Yang, Da Xing (2011)

Autophagy and apoptosis play important roles in the development, cellular homeostasis and, especially, oncogenesis of mammals. They may be triggered by common upstream signals, resulting in combined autophagy and apoptosis. In other instances, they may be mutually exclusive. Recent studies have suggested possible molecular mechanisms for crosstalk between autophagy and apoptosis. Bcl-2 and Bcl-xL, the well-characterized apoptosis guards, appear to be important factors in autophagy, inhibiting Beclin 1-mediated autophagy by binding to Beclin 1. In addition, Beclin 1, Bcl-2 and Bcl-xL can cooperate with Atg5 or Ca(2+) to regulate both autophagy and apoptosis. Thus, Bcl-2 and Bcl-xL represent a molecular link between autophagy and apoptosis. Here, we discuss the possible roles of Bcl-2 and Bcl-xL in apoptosis and autophagy, and the crosstalk between them. © 2010 The Authors Journal compilation © 2010 FEBS.

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Journal

Journal ID (nlm-ta): Neural Regen Res

Journal ID (iso-abbrev): Neural Regen Res

Journal ID (publisher-id): NRR

Title: Neural Regeneration Research

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 1673-5374

ISSN (Electronic): 1876-7958

Publication date (Print): March 2018

Volume: 13

Issue: 3

Pages: 556-562

Affiliations

[1 ]Xiangya Medical School, Central South University, Changsha, Hunan Province, China

[2 ]Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China

Author notes

[* ] Correspondence to: Kun Xiong, xiongkun2001@ 123456163.com .

[#]

These authors contributed equally to this paper.

Author contributions: SYC, SCW and ML wrote the first draft of the paper. KX and ZW coordinated the work and revised the paper. All authors approved the final version of the paper.

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Kun Xiong http://orcid.org/0000-0002-3103-6028

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Publisher ID: NRR-13-556

DOI: 10.4103/1673-5374.228762

PMC ID: 5900522

PubMed ID: 29623944

SO-VID: e2a8ff43-a6d6-4ae5-9fbe-ec302c5b96d4

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Regulatory role of calpain in neuronal death

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Neuronal Signaling

Most cited references 88

Autophagy and apoptosis dysfunction in neurodegenerative disorders.

Novel targets for Huntington's disease in an mTOR-independent autophagy pathway.

Bcl-2 and Bcl-xL play important roles in the crosstalk between autophagy and apoptosis.

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