Involvement of Calpain Activation in Neurodegenerative Processes

Abstract

One of the challenges in the coming years will be to better understand the mechanisms of neuronal cell death with the objective of developing adequate drugs for the treatment of neurodegenerative disorders. Caspases and calpains are among the best-characterized cysteine proteases activated in brain disorders. Likewise, during the last decade, extensive research revealed that the deregulation of calpains activity is a key cytotoxic event in a variety of neurodegenerative disorders. Moreover, interest in the role of calpain in neurodegenerative processes is growing due to implication of the involvement of cdk5 in neurodegenerative diseases. Since calpain inhibitors appear to not only protect brain tissue from ischemia, but also to prevent neurotoxicity caused by such neurotoxins as â-amyloid or 3-nitropropionic acid, the currently available data suggest that calpain and cdk5 play a key role in neuronal cell death. It seems clear that the inappropriate activation of cysteine proteases occurs not only during neuronal cell death, but may also contribute to brain pathology in ischemia and traumatic brain disorders. Pharmacological modulation of calpain activation may, therefore, be useful in the treatment of neurodegenerative disorders. It is possible, although difficult, to develop synthetic inhibitors of cysteine proteases, specifically calpains. The inhibition of calpain activation has recently emerged as a potential therapeutic target for the treatment of neurodegenerative diseases. 135

Programmed Cell Death in Parkinson's Disease

“…Moreover, Cdk5 phosphorylation of Parkin regulates its ubiquitin-ligase activity and protein aggregation (Avraham et al 2007). a-Synuclein is another one of many other Cdk5 substrates (see reviews by Camins et al 2006;Cheung and Ip 2011;Lopes and Agostinho 2011).…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…Moreover, extrasynaptic NMDAR activity induces calpainmediated cleavage of Myocyte enhancer factor 2 (MEF2), glutamic acid decarboxylase (GAD65/67), Fodrin, NCX3, and STEP (Xu et al, 2009a,b;Monnerie et al, 2010;Wei et al, 2012). activation of calpains by the intracellular calcium overload in brain ischemia and in excitotoxic conditions (Camins et al, 2006;Bevers and Neumar, 2008) leads to the cleavage of plasma membrane proteins (Lu et al, 2000;Neumar et al, 2001;Rong et al, 2001;Yuen et al, 2007;Gomes et al, 2012), synaptic vesicle proteins Lobo et al, 2011), transporters (Bano et al, 2005;Pottorf et al, 2006), mitochondrial proteins (Takano et al, 2005) and many other substrates (Bevers and Neumar, 2008). Lipases are also activated by calcium, further increasing the production of free radical species (Farooqui and Horrocks, 1994).…”

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

“…These phenomena were also confirmed in cortical neuron cultures treated with another neurotoxic molecule, rotenone (data not shown), suggesting that regulation of tAIF by Cdk5-mediated phosphorylation of CHIP comprises one of the key steps to determine neuronal death. In both of cell death paradigms, neurotoxin-induced activation of Cdk5 is accompanied with a time-dependent generation of p25, potentially by activated calpain, 50,51 leading to increased level of phosphorylated CHIP at Ser20 and concomitant appearance of tAIF. Thus, our data support the notion that neurotoxic stimuli-induced tAIF generation is critically linked to neuronal death involved in cortical neurodegeneration and this phenomenon is regulated by Cdk5-mediated phosphorylation of CHIP at Ser20.…”