Abstract
Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.
Highlights
This review has focused on CDGSH iron-sulfur domain 2 (CISD2) as a unique zinc finger and iron-sulfur protein and emphasized its protective role against Nuclear factor κB (NFκB) activation
It is worth noting that the inflammation and mitochondrial dysfunction caused by CISD2 decline are widely involved in neurodegenerative states and neurotrauma
Several factors susceptible to this disease category include genetics, aging, and the environment, which may lead to abnormal aggregation of misfolded proteins in the central nervous system (CNS) (Figure 1) and further trigger neuroinflammation, mitochondrial dysfunction, neuronal loss, and eventual neurological deficits
Summary
In the pathogenesis of NDs, various microneural abnormalities are involved in structural and functional impairment or loss of CNS neural networks such as enhanced permeability of the blood-brain barrier, damaged axons or myelin sheaths, dysregulated immune activation (innate and adaptive), and neuronal insults [5,6]. The abnormally folded/aggregated proteins underlying NDs include hyperphosphorylated tau, Aβ-peptide (for AD), α-synuclein (for PD), huntingtin (for Huntington disease), and prion (for prion diseases) [17]. Based on this immunocompetent response, aggregation of pattern recognition receptors (PRRs), which are mainly toll-like receptors (TLRs), activate microglia and trigger neuroinflammation [18]. Pro-caspase-1 activation and subsequent production of proinflammatory cytokines (IL-1β, IL-18) combined with microglial TLR-9 lead to the profound release of proinflammatory mediators [28] This vicious cascade may expand with the release of more mitochondrial DAMPs, more enhanced inflammasome activation, and more extensive glial neuroinflammation [29].
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