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Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Calpain 3 (LGMD D4/R1) is a muscle-specific protease that has an important role in regulating other proteases as well as signaling pathways. It also interacts with dysferlin and may have a role in membrane resealing. TRIM32 (LGMD R8) is thought to play a role in the ubiquitin–proteasome pathway that is important for protein degradation.
Neurology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Fenella Kirkham, Adnan Manzur, Stephanie Robb
Limb girdle dystrophies (LGMD) (Figs 8.55, 8.60): dominant and recessive forms, many subtypes, some present in adulthood.abnormalities of: – lamin A/C (Emery–Dreifuss dystrophy (EDMD)) (Figs 8.60 C,D 8.26 C,D).– calpain 3 (Figs 8.60 E,F).– sarcoglycans (Figs 8.60 A,B,G,D).– FKRP.– collagen VI (Bethlem myopathy).
Diseases of Muscle and the Neuromuscular Junction
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Chris Turner, Anthony Schapira
Dilated cardiomyopathy and neuromuscular respiratory failure may develop in some patients with LGMD, usually after the onset of limb girdle weakness. Other muscle groups may also be affected such as periscapular involvement in LGMD caused by mutations in FKRP or calpain-3.
Modulators of calpain activity: inhibitors and activators as potential drugs
Published in Expert Opinion on Drug Discovery, 2020
Levente Endre Dókus, Mo’ath Yousef, Zoltán Bánóczi
Although more unconventional calpains have been identified lately, their physiological functions are poorly described. One of the most studied isoforms is calpain 3, which is especially abundant in skeletal muscle. Unlike calpain 1 and 2, this isoform is a homodimer, thus the small regulatory unit is not necessary for its activity [42]. The structure of its protease core domain has been determined [43]. Although our knowledge about its physiological role is not complete, its missing activity (proteolytic and non-proteolytic), caused by mutation, is responsible for muscular dystrophies (e.g. limb-girdle muscular dystrophy type 2A (LGMD2A)) [42]. Calpain 5 is mainly expressed in the retina and in the synapses of photoreceptors. Similarly, to calpain 3, our knowledge is restricted about its normal function, but several mutations are known which disturb its activity and thus result in pathological alterations (e.g. vitreoretinopathy) [44,45]. Meanwhile, calpains 8 and 9 are dominantly expressed in the stomach. Mice without these enzymes are susceptible to ethanol-induced gastric ulcers, indicating that both proteins play protective roles in the gastric mucosa [46]. These enzymes form a protease complex, ‘G-calpain’ with dual enzyme activity. Calpain 10 is a non-classical calpain and was proved to be the first susceptibility gene for type 2 diabetes mellitus. There is evidence that it has a role in insulin secretion and insulin-stimulated glucose uptake [47].
Calpain-2 as a therapeutic target for acute neuronal injury
Published in Expert Opinion on Therapeutic Targets, 2018
Yubin Wang, Xiaoning Bi, Michel Baudry
While calcium-activated neutral proteases (CANP) were discovered in 1964 by Guroff [1], the terms calpain and calpastatin, its endogenous inhibitor, were introduced in the 1980s [2]. Since then, many studies have been directed at understanding the physiological as well as the pathological function(s) of this family of proteases in the brain and other organs. We initially proposed in 1984 that calpain played a critical role in synaptic plasticity and learning and memory [3], and this hypothesis was recently confirmed by studies performed in calpain-1 knock-out (KO) mice [4,5]. Since the original hypothesis was proposed, studies related to the functions of calpain in the brain have mostly focused on the potential critical roles of calpain in neuronal death and neurodegeneration [6–13]. While there is strong evidence that calpain plays a role in neurodegeneration, the major issue plaguing the literature is that there are only a handful of studies addressing the question of which calpain isoform(s) is (are) involved and of the signaling pathways leading to neurodegeneration. Since the identification of calcium-dependent neutral proteases by Guroff [1], a plethora of calpain isoforms have been identified and we now know that calpains constitute a family of enzymes with at least 15 members [14,15]. Several studies have addressed the specific roles each of these proteases play in human diseases [16]. Defects in the gene encoding the muscle-specific calpain-3 lead to a particular type of dystrophy, limb-girdle muscular dystrophy 2A (LGMD-2A) [17,18]. However, calpain-3 has a number of unique features, which set it apart from the more typical calpain isoforms [19]. There is also good evidence for a link between calpain-10 and diabetes mellitus, based on genetic studies [20]. More recently, calpain-14 has been linked to eosinophilic esophagitis, due to its abundance in the upper gastrointestinal tract [21]. In the brain, the major calpain isoforms are calpain-1, aka µ-calpain, calpain-2, aka m-calpain, and calpain-5. Mutations of calpain-5 have recently been associated with autoimmune uveitis and photoreceptor degeneration [22]. We previously reviewed the roles of calpain in synaptic plasticity, and this topic will not be addressed here [4]. The present review will focus on the role calpain-2 is playing in acute neuronal death and on the mechanisms linking calpain-2 activation to neuronal death. It will also review the evidence indicating that calpain-2 is a good target to develop selective inhibitors, which could be developed for the treatment of various neurological disorders associated with acute neuronal death. Finally, we will discuss the possibility that these inhibitors could also be useful for the treatment of chronic neurodegenerative disorders.