Calpain signaling: from biology to therapeutic opportunities in neurodegenerative disorders

Abstract

Neurodegenerative disorders represent a major and growing healthcare challenge globally. Among the numerous molecular pathways implicated in their pathogenesis, calpain signaling has emerged as a crucial player in neuronal dysfunction and cell death. Calpain is a family of calcium-dependent cysteine proteases that is involved in many biological processes, such as signal transduction, cytoskeleton remodeling, and protein turnover. Dysregulation of calpain activation and activity has been associated with several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Understanding the intricate structure of calpains is crucial for unraveling their roles in cellular physiology and their implications in pathology. In addition, the identification of diverse abnormalities in both humans and other animal models with deficiencies in calpain highlights the significant progress made in understanding calpain biology. In this comprehensive review, we delve into the recent roles attributed to calpains and provide an overview of the mechanisms that govern their activity during the progression of neurodegenerative diseases. The possibility of utilizing calpain inhibition as a potential therapeutic approach for treating neuronal dysfunctions in neurodegenerative disorders would be an area of interest in future calpain research.

Mitochondrial Dysfunction as the Major Basis of Brain Aging

“…These chronic neuroinflammatory responses lead to neuronal loss [17]. Inhibition of calpain diminishes microglial and astroglial responsivity and reduces the extent of the neuropathological changes and behavioral decline of aged transgenic mice modeling Alzheimer's disease [18][19][20] and Parkinson's disease [21,22]. Glutamate receptors that respond to excess activation are also found in oligodendrocytes which can be damaged by excitotoxic events [23].…”

Biomaterials targeting the microenvironment for spinal cord injury repair: progression and perspectives

“…Furthermore, combination therapy facilitates the formation of myelin in nerve fibers and augments synaptic connectivity ( Giorgi et al, 2024 ). Notably, the reduction in astrocyte formation and the secretion of CSPGs by glial cells plays a significant role in mitigating fibrosis during the acute phase of SCI and in the subsequent formation of glial scars ( Metwally et al, 2023 ).…”

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

“…Calpain, an intracellular non-lysosomal neutral protease, is involved in different cellular processes, including neuronal remodeling, axon degeneration, apoptosis, cellular proliferation, and cell motility [27,112]. The excessive activation of calpain influences several pathways, such as neuroinflammation, ROS, apoptosis, and autophagy [21,24,113,114].…”

“…There are a number of calpain isoforms, but calpain-1 and calpain-2 are ubiquitously expressed in the CNS. Calpain-1 is activated by micromolar (µ) calcium levels, while calpain-2 is activated by millimolar (m) calcium levels [27]. Once activated, calpain is thought to cleave α-syn.…”

“…This activation occurs when α-syn binds to integrin CD11b, which then activates the downstream Rho-ROCK pathway [23]. A number of studies have suggested that the over-activation of calpain, which is a calcium-dependent non-lysosomal cysteine protease, may play a critical role in the onset and/or progression of several neurodegenerative diseases [21,[24][25][26][27]. The over-activation of calpain may also affect the downstream Rho-ROCK pathway.…”