Calpain activation and progression of inflammatory cycles in Parkinson's disease
- PMID: 35090325
- PMCID: PMC9723550
- DOI: 10.31083/j.fbl2701020
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 (Ca2+) influx, oxidative stress and damage to the blood brain barrier (BBB). Dysfunctional mitochondria destabilize cytosolic Ca2+ concentrations, raising intracellular Ca2+; 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.
Keywords: Calpain; Dopamine; Neurodegeneration; Neuroinflammation; Parkinson's disease (PD); Spinal cord; α-Synuclein (α-Syn).
© 2022 The Author(s). Published by IMR Press.
Conflict of interest statement
The authors declare no conflict of interest. AH is serving as one of the Editorial Board members of this journal. We declare that AH had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to GP.
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References
-
- Vivacqua G, Biagioni F, Yu S, Casini A, Bucci D, D’Este L, et al. Loss of spinal motor neurons and alteration of alpha-synuclein immunostaining in MPTP induced Parkinsonism in mice. Journal of Chemical Neuroanatomy. 2012. ; 44: 76–85. - PubMed
-
- Del Tredici K, Braak H. Spinal cord lesions in sporadic Parkinson’s disease. Acta Neuropathologica. 2012. ; 124: 643–664. - PubMed
-
- Salat D, Tolosa E. Levodopa in the treatment of Parkinson’s disease: current status and new developments. Journal of Parkinson’s Disease. 2013. ; 3: 255–269. - PubMed
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