Calpain activation and progression of inflammatory cycles in Parkinson’s disease

Abstract

Parkinson's disease (PD) is a progressive, neurodegenerative condition of the central nervous system (CNS) affecting 6.3 million people worldwide with no curative treatments. Current therapies aim to mitigate PD's effects and offer symptomatic relief for patients. Multiple pathways are involved in the pathogenesis of PD, leading to neuroinflammation and the destruction of dopaminergic neurons in the CNS. This review focuses on PD pathology and the role of calpain, a neutral protease, as a regulator of various immune cells such as T-cells, microglia and astrocytes which lead to persistent neuroinflammatory responses and neuronal loss in both the brain and spinal cord (SC). Calpain plays a significant role in the cleavage and aggregation of toxic α-synuclein (α-syn), a presynaptic neural protein, and other organelles, contributing to mitochondrial dysfunction and oxidative stress. α-Syn aggregation results in the formation of Lewy bodies (LB) that further contribute to neuronal damage through lipid bilayer penetration, calcium ion (Ca 2+ ) influx, oxidative stress and damage to the blood brain barrier (BBB). Dysfunctional mitochondria destabilize cytosolic Ca 2+ concentrations, raising intracellular Ca 2+ ; this leads to excessive calpain activation and persistent inflammatory responses. α-Syn aggregation also results in the disruption of dopamine synthesis through phosphorylation of tyrosine hydroxylase (TH), a key enzyme involved in the conversion of tyrosine to levodopa (L-DOPA), the amino acid precursor to dopamine. Decreased dopamine levels result in altered dopamine receptor (DR) signaling, ultimately activating pro-inflammatory T-cells to further contribute to the inflammatory response. All of these processes, together, result in neuroinflammation, degeneration and ultimately neuronal death seen in PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-a prodrug to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+)), rotenone (an environmental neurotoxin), and 6-hydroxydopamine (6-OHDA -a neurotoxic synthetic organic compound) induce PD-like conditions when injected into rodents. All three agents work through similar mechanisms and lead to degeneration of dopaminergic neurons in the substantia nigra (SN) and more recently discovered in motor neurons of the spinal cord (SC). These neurotoxins also increase calpain activity, furthering the neuroinflammatory response. Hence, calpain inhibitors have been posited as potential therapeutics for PD to prevent calpain-related inflammation and neurodegenerative responses in not only the SN but the SC as well.

Changes in calpain-2 expression during glioblastoma progression predisposes tumor cells to temozolomide resistance by minimizing DNA damage and p53-dependent apoptosis

“…Instead of merely proteolytically degrading their substrates, they often modulate protein activity in cell motility, cell adhesion, autophagy and apoptosis (reviewed in [6,9]). Moreover, calpain proteases are involved in various disorders such as Alzheimer's disease [16][17][18], Parkinson's disease [19], glioma [20], colorectal cancer [21,22], acute myeloid leukaemia [23], or breast cancer [24,25]. In a recent study, calpain-1 activity was used to stain glioblastoma during surgical intervention leading to a spatial distinction between tumor and peritumoral tissue [26].…”

Complement Cascade 8 - Alpha and Calpain-2 in Extracellular Vesicles of Human Vitreous as Biomarkers of Infectious Endophthalmitis

“…We hypothesize that the lower cargo of calpain-2 in the EVs and in vitreous could attribute to its neuroprotective role in the humans. 22 Furthermore, regulating excess inflammation could also preserve retinal architecture thereby preventing vision loss. Complement component is a core part of immune system, and C8α is a part of MAC that is responsible for pathogen killing and controlling infection.…”

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].…”