Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death

Abstract

Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years led to the remarkable conclusion that these two calpain isoforms exhibit opposite functions in the brain. Calpain-1 activation is required for certain forms of synaptic plasticity and corresponding types of learning and memory, while calpain-2 activation limits the extent of plasticity and learning. Calpain-1 is neuroprotective both during postnatal development and in adulthood, while calpain-2 is neurodegenerative. Several key protein targets participating in these opposite functions have been identified and linked to known pathways involved in synaptic plasticity and neuroprotection/neurodegeneration. We have proposed the hypothesis that the existence of different PDZ (PSD-95, DLG and ZO-1) binding domains in the C-terminal of calpain-1 and calpain-2 is responsible for their association with different signaling pathways and thereby their different functions. Results with calpain-2 knock-out mice or with mice treated with a selective calpain-2 inhibitor indicate that calpain-2 is a potential therapeutic target in various forms of neurodegeneration, including traumatic brain injury and repeated concussions.

Revisiting Excitotoxicity in Traumatic Brain Injury: From Bench to Bedside

“…Calpains are Ca 2+ -activated neutral proteases involved in multiple pathways such as remodeling, cell signaling, synaptic plasticity, neuroprotection, learning, and programmed cell death [65,66]. Evidence suggests calpains are early regulators of cell death after TBI.…”

“…Wang and colleagues [67] showed calpain-2 is responsible for NMDA-induced excitotoxicity through the activation of striatal-enriched protein tyrosine phosphatase (STEP) when extra synaptic NMDA receptors are activated in rat-cultured neurons. STEP activation mediated by calpain-2 results in p38 expression and, therefore, downstream cell death [65,68]. After TBI, high [Ca 2+ ] i , OS, and ischemia, induce endoplasmic reticulum (ER) stress, which oversees membrane protein synthesis, folding, and quality control.…”

Calpains for dummies: What you need to know about the calpain family

“…Of note, this might be related to a deleterious effect of the loss of function of this protease during development as shown by the fact that calpain-2 knock-out mice are embryonic lethal, suggesting the possibility of non-detected embryonic lethal CAPN2 mutations in humans [163,164]. Recently, it has also been proposed that CAPN1 and CAPN2 play opposite role in the brain: a neuroprotective action from calpain-1 and a neurodegenerative effect from calpain-2 [12,165,166] Finally, this year, several variants in CAPN15 have been associated with developmental eye disorders [90]. Loss of function mutations were identified in patients from 4 different families, presenting with microphthalmia and/or coloboma (disruption of the optic fissure closure).…”

Targeted proteolytic products of τ and α-synuclein in neurodegeneration

“…Calpains are highly conserved, calcium-dependent cysteine proteases that have been linked to neurodegeneration in AD [ 39 ]. Current evidence suggests that calpain-1 activity is important for physiologic development of synaptic plasticity, learning and memory, while calpain-2 is related to synaptic plasticity and neuronal death [ 40 ]. However, dysregulation of both calpain-1 and calpain-2 activity can lead to improper processing and proteolysis of τ protein, which generates different τ fragments.…”