The calcium-dependent protease calpain in neuronal remodeling and neurodegeneration

Calpains are evolutionally conserved and widely expressed cysteine proteases that act at neutral pH. Unlike all other proteases, calpains are activated by Ca2+. Under physiological conditions, cytoplasmic Ca2+ levels are typically in the μM range, which is much lower than the mM Ca2+ levels required for calpain activation in in vitro assays. Accordingly, how calpain is activated under physiological conditions has been a critical and long-standing question in the field. A critical player in the activation of calpain appears to be Ttm50. Ttm50, a subunit of the TIM23 complex involved in the transport of proteins across the mitochondrial inner membrane, anchors calpain to Golgi/endoplasmic reticulum Ca2+ stores, while simultaneously increases the calcium sensitivity of calpain by directly interacting with calpain via its C-terminal FCP1 domain. Calpains are activated by calcium transients in neuronal remodeling during development and by calcium overload in Wallerian degeneration and neurodegenerative diseases. Given that axon loss is often an early sign of neurodegeneration, its prevention by inhibiting calpain activity may lead to treatments for neurodegenerative diseases. Calpains are evolutionarily conserved and widely expressed Ca2+-activated cysteine proteases that act at neutral pH. The activity of calpains is tightly regulated, given that their abnormal activation can have deleterious effects leading to promiscuous cleavage of various targets. Genetic mutations in the genes encoding calpains are associated with human diseases, while abnormally elevated Ca2+ levels promote Ca2+-dependent calpain activation in pathologies associated with ischemic insults and neurodegeneration. In this review, we discuss recent findings on the regulation of calpain activity and activation as revealed through pharmacological, genetic, and optogenetic approaches. Furthermore, we highlight studies elucidating the role of calpains in dendrite pruning and axon degeneration in the context of Ca2+ homeostasis. Finally, we discuss future directions for the study of calpains and potential therapeutic strategies for inhibiting calpain activity in neurodegenerative diseases. Calpains are evolutionarily conserved and widely expressed Ca2+-activated cysteine proteases that act at neutral pH. The activity of calpains is tightly regulated, given that their abnormal activation can have deleterious effects leading to promiscuous cleavage of various targets. Genetic mutations in the genes encoding calpains are associated with human diseases, while abnormally elevated Ca2+ levels promote Ca2+-dependent calpain activation in pathologies associated with ischemic insults and neurodegeneration. In this review, we discuss recent findings on the regulation of calpain activity and activation as revealed through pharmacological, genetic, and optogenetic approaches. Furthermore, we highlight studies elucidating the role of calpains in dendrite pruning and axon degeneration in the context of Ca2+ homeostasis. Finally, we discuss future directions for the study of calpains and potential therapeutic strategies for inhibiting calpain activity in neurodegenerative diseases. self-destruction process resulting in axon loss in different settings of development, injury, and disease, including Wallerian degeneration typically induced by axotomy. intracellular Ca2+ levels in different cell types are maintained in an appropriate range depending on the status of the cell: resting state or activated. Among the primary routes of neuronal Ca2+ entry and egress are voltage-gated Ca2+ channels (VGCCs), potassium-dependent Na+/Ca2+ exchangers (NCKs), and plasma membrane Ca2+ ATPases (PMCAs). To maintain Ca2+ homeostasis, the same amount of Ca2+ that enters the cytoplasm through VGCCs upon activation must be removed by NCKs and PMCAs in the resting state. Likewise, the same amount of Ca2+ that is released from Ca2+ stores by ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptor (IP3R) is taken back by the SERCA pump. intracellular organelles that store Ca2+, such as the ER, Golgi, and mitochondria. The Ca2+ concentration in the stores is ~100 μM–1 mM, whereas the concentration in the cytoplasm in the resting state is ~100 nM. a transient increase in Ca2+ in the cytoplasm upon stimulation or excitation. a process by which neurons selectively remove exuberant or unnecessary dendrites without causing cell death. The process is crucial for the establishment of mature neural circuits during animal development. proteins activated by a range of stimuli and mediating several physiological and pathological cellular functions. For example, activation of MAPK represents an early degenerative response to axon injury. MAPK signaling promotes the degradation of palmitoylated nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), while genetic or pharmacological inhibition of MAPK signaling results in upregulated NMNAT2 levels and axon protection. progressive loss of structure or function of neurons, including neuronal death. Prominent examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Such diseases are incurable, resulting in progressive degeneration of neurons. used to describe multiple biological processes, including synapse elimination or strengthening, dendrite and axon elimination, and programmed cell death of specific neuronal populations. Remodeling involves specific elimination of existing connections, typically followed by strengthening of surviving synapses or neurite regrowth to form new connections. a protein with NAD+ hydrolase activity both required and sufficient for axon degeneration. Sarm1 initiates a local axon destruction program involving rapid breakdown of NAD+ after injury. a protein complex with multiple subunits in the inner mitochondrial membrane involved in protein import into the mitochondrial matrix. a specific form of genetically programmed axon degeneration in disease and injury. Active Wallerian degeneration requires Sarm1, while the NAD+ synthetic enzyme NMNAT2 prevents degeneration. Some of the mechanisms identified in Wallerian degeneration may also operate during axon elimination in development.