CAPN1

CAPN1 Background

The CAPN1 encodes calpain-1, one isoform of calpains that are calcium-activated cytosolic cysteine proteases. CAPN1 is ubiquitously expressed in the central nervous system (CNS) of mammalian cells^[1]. Calpain exists as an inactive proenzyme in the cytosol and migrates to membranes in response to the increase of cellular calcium ion concentration ^[2]. At the membrane, calpain is activated in the presence of calcium ion and phospholipids ^[3]. Calpain activation in apoptosis was first demonstrated in thymocytes, as measured by calpain autolysis ^[4]. Activated calpain leads to apoptosis by mediating the degradation of various proteins involved in maintaining neuronal structural integrity essential for normal cellular function and survival ^[5]. Calpain-1 is activated by micromolar concentrations of calcium. The activation of calpain-1 promotes neuronal survival (namely neuroprotection) ^[6] and synaptic plasticity ^[8][10]. Synaptic Nmethyl- D-asparate (NMDA) receptor-induced activation of calpain-1 degraded both PHLPP1α and PHLPP1β, leading to activation of the Akt ＆ ERK pathways and neuroprotection ^[6][7]. Other findings also revealed the physiological role of calpain-1 in the regulation of calcium influx, apoptosis of primary neurons subjected to oxidative stress, and neuronal death following traumatic brain injury ^[14]. Targeted inhibition of calpain-1 offers a potential therapeutic approach against TBI and other neurodegenerative diseases ^[14]. Mutations in CAPN1 have recently been identified in a complicated form of Hereditary Spastic Paraplegia (HSP) with a combination of cerebellar ataxia and corticomotor tract disorder(SPG76) ^[9]. Overactivation of calpain-1 causes irreversible cell damage and contributes to the pathology of cerebral and cardiac ischemia, Alzheimer's disease, arthritis, and cataract formation ^[10][11]. Yoko Nabeshima et al. proposed that regulation of calpain-1 activity is a potential therapeutic target for drug development towards delaying onsets of aging-related syndromes caused by the abnormality of mineral homeostasis and reducing the complications of CKD ^[13].

[1] Ohno S, Minoshima S, et al. Four genes for the calpain family located on four distinct human chromosomes [J]. Cytogenet Cell Genet. 1990, 53 (4): 225-9.
[2] Wingrave JM, Schaecher KE, et al. Early induction of secondary injury factors causing activation of calpain and mitochondria-mediated neuronal apoptosis following spinal cord injury in rats [J]. J Neurosci Res. 2003 Jul 1; 73(1):95-104.
[3] Suzuki K, Sorimachi H. A novel aspect of calpain activation [J].FEBS Lett. 1998 Aug 14; 433(1-2):1-4.
[4] Squìer MK, Miller AC, et al. Calpain activation in apoptosis [J]. J Cell Physiol. 1994 May; 159(2):229-37.
[5] Springer JE, Azbill RD, et al. Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment [J]. J Neurochem. 1997 Oct; 69 (4):1592-600.
[6] Wang Y, et al. Distinct roles for mu-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration [J]. J Neurosci. 2013;33(48):18880-92.
[7] Averna M, Pellegrini M, et al. Physiological roles of calpain 1 associated to multiprotein NMDA receptor complex [J]. PLoS ONE. 2015, 10:e0139750.
[8] Liu J, Liu MC, et al. Calpain in the CNS: from synaptic function to neurotoxicity [J]. Sci Signal. 2008 Apr 8; 1(14):re1.
[9] Stefano Cotti Piccinelli, Maria T. Bassi, et al. A Novel CAPN1 Mutation Causes a Pure Hereditary Spastic Paraplegia in an Italian Family [J]. Front Neurol. 2019; 10: 580.
[10] Baudry M, Bi X. Calpain-1 and calpain-2: the Yin and Yang of synaptic plasticity and neurodegeneration [J]. Trends Neurosci. 2016, 39:235-45.
[11] Wang, K. K. & Yuen, P. W. Calpain inhibition: an overview of its therapeutic potential [J]. Trends Pharmacol. Sci. 15, 1994, 412-419.
[12] Lee, M. S. et al. Neurotoxicity induces cleavage of p35 to p25 by calpain [J]. Nature 405, 2000, 360-364.
[13]Yoko Nabeshima, Miwa Washida, et al. Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes [J]. Scientific Reports volume 4, 2015, Article number: 5847.
[14] Kaori H. Yamada, Dorothy A. Kozlowski, et al. Targeted Gene Inactivation of Calpain-1 Suppresses Cortical Degeneration Due to Traumatic Brain Injury and Neuronal Apoptosis Induced by Oxidative Stress [J]. The Journal of Biological Chemistry, 2012, 287, 13182-13193.