Cisd2: a promising new target in Alzheimer's disease^†

Abstract

The CISD2 gene encodes the CDGSH iron‐sulfur domain‐containing protein 2. Cisd2 is involved in mammalian lifespan control, the unfolded protein response, Ca2+ buffering, and autophagy regulation. It has been demonstrated previously that Cisd2 deficiency causes an accelerated ageing phenotype characterised by the accumulation of damaged mitochondria, while Cisd2 overexpression leads to mitochondrial protection against typical age‐associated alterations. Accumulating data suggest that neuronal amyloid‐beta (Aβ) deposition, Ca2+ dysregulation, impairment of autophagic flux, and accumulation of damaged organelles including mitochondria play an important role in Alzheimer's disease (AD) pathogenesis. In a recent issue of The Journal of Pathology, Yi‐Fan Chen and collaborators put together all these experimental observations and demonstrated that Cisd2 overexpression attenuates AD pathogenesis by guaranteeing mitochondrial quality and synaptic functions. The authors report convincing evidence to highlight the role of Cisd2 in Aβ‐mediated mitochondrial damage and, interestingly, this neuroprotection could be dependent on other molecular mechanisms beyond the canonical and previously described roles of Cisd2. Collectively, these data open up new avenues in neuroprotection and highlight Cisd2 as a promising new target in AD. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Iron Metabolism in Aging and Age-Related Diseases

“…A recent analysis shows that iron levels and related redox activities in the cortex and cerebellum were increased in patients in the preclinical stage of AD [ 89 ]. As the Cisd2 gene encodes the CDGSH iron–sulfur-domain-containing protein 2, Cisd2 overexpression attenuates AD pathogenesis by guaranteeing mitochondrial quality and synaptic functions [ 91 ]. Therefore, brain iron accumulation has become a major pathological feature of the early onset of AD.…”

High Expression of CISD2 in Relation to Adverse Outcome and Abnormal Immune Cell Infiltration in Glioma

“…High CISD2 expression was significantly correlated with poor prognosis in different tumors. In gastric cancer, CISD2 is significantly upregulated and is markedly associated with clinical stage, venous invasion, TNM classification, and lymphatic invasion [ 46 ]. Yang et al [ 40 ] found that CISD2 expression was abnormally upregulated in human laryngeal squamous cell carcinoma tissues and was remarkably correlated with T stage, lymphatic invasion, clinical stage, and progress of the disease.…”

A Simplified Method for the Histochemical Detection of Iron in Paraffin Sections: Intracellular Iron Deposits in Central Nervous System Tissue

“…CISD2 KO mice not only recapture these phenotypes but also present nerve and muscle degeneration in association with mitochondrial damage, and autophagy-mediated cell death (Chen et al. 2009a; 2009b; Nobili et al., 2020). In addition, the lysosome is used in the cellular uptake of iron, and the lysosome and other structures associated with autophagy (e.g., autophagosome) are essential for the recycling of iron (Kurz et al., 2011).…”