Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases

Zhi Dong Zhou, Eng-King Tan

The homeostasis of iron is vital to human health, and iron dyshomeostasis can lead to various disorders. Iron homeostasis is maintained by iron regulatory proteins (IRP1 and IRP2) and the iron-responsive element (IRE) signaling pathway. IRPs can bind to RNA stem-loops containing an IRE in the untranslated region (UTR) to manipulate translation of target mRNA. However, iron can bind to IRPs, leading to the dissociation of IRPs from the IRE and altered translation of target transcripts. Recently an IRE is found in the 5'-UTR of amyloid precursor protein (APP) and α-synuclein (α-Syn) transcripts. The levels of α-Syn, APP and amyloid β-peptide (Aβ) as well as protein aggregation can be down-regulated by IRPs but are up-regulated in the presence of iron accumulation. Therefore, inhibition of the IRE-modulated expression of APP and α-Syn or chelation of iron in patient's brains has therapeutic significance to human neurodegenerative diseases. Currently, new pre-drug IRE inhibitors with therapeutic effects have been identified and are at different stages of clinical trials for human neurodegenerative diseases. Although some promising drug candidates of chemical IRE inhibitors and iron-chelating agents have been identified and are being validated in clinical trials for neurodegenerative diseases, future studies are expected to further establish the clinical efficacy and safety of IRE inhibitors and iron-chelating agents in patients with neurodegenerative diseases.