Iron-responsive-like elements and neurodegenerative ferroptosis

Abstract

A set of common-acting iron-responsive 5′untranslated region (5′UTR) motifs can fold into RNA stem loops that appear significant to the biology of cognitive declines of Parkinson's disease dementia (PDD), Lewy body dementia (LDD), and Alzheimer's disease (AD). Neurodegenerative diseases exhibit perturbations of iron homeostasis in defined brain subregions over characteristic time intervals of progression. While misfolding of Aβ from the amyloid-precursor-protein (APP), alpha-synuclein, prion protein (PrP) each cause neuropathic protein inclusions in the brain subregions, iron-responsive-like element (IRE-like) RNA stem–loops reside in their transcripts. APP and αsyn have a role in iron transport while gene duplications elevate the expression of their products to cause rare familial cases of AD and PDD. Of note, IRE-like sequences are responsive to excesses of brain iron in a potential feedback loop to accelerate neuronal ferroptosis and cognitive declines as well as amyloidosis. This pathogenic feedback is consistent with the translational control of the iron storage protein ferritin. We discuss how the IRE-like RNA motifs in the 5′UTRs of APP, alpha-synuclein and PrP mRNAs represent uniquely folded drug targets for therapies to prevent perturbed iron homeostasis that accelerates AD, PD, PD dementia (PDD) and Lewy body dementia, thus preventing cognitive deficits. Inhibition of alpha-synuclein translation is an option to block manganese toxicity associated with early childhood cognitive problems and manganism while Pb toxicity is epigenetically associated with attention deficit and later-stage AD. Pathologies of heavy metal toxicity centered on an embargo of iron export may be treated with activators of APP and ferritin and inhibitors of alpha-synuclein translation.

Targeting RNA structures with small molecules

“…IRP binding to IREs in the 5′UTR prevents ribosome docking and blocks RNA translation whereas binding to the 3′UTR stabilizes the transcript and upregulates translation 202 . IREs have an important role in cognitive function and hence in neuro degenerative diseases [203][204][205][206][207] . Small molecules that target IREs and inhibit the translation of these pathogenic proteins have been discovered 13,197,[208][209][210][211][212][213] .…”

Parkinson's disease: Alterations in iron and redox biology as a key to unlock therapeutic strategies

“…There is also some sequence similarities comparing the 5ꞌ UTRs of the α-synuclein and APP transcripts, another comparison that provides a further link between these proteinopathies [ 394 , 399 , 400 ]. It has been speculated for both PD and Alzheimer's disease that the atypical IRE sequences in α-synuclein and APP may be responsive to excess brain iron in a potential feedback loop to accelerate neuronal ferroptosis (a form of iron-mediated cell death) leading to cognitive decline and proteinopathy [ 401 ]. However, β-amyloid and α-synuclein rarely co-localize in brain amyloid deposits [ 402 ].…”

Neurometals in the Pathogenesis of Prion Diseases

“…It is widely known that the translation of various genes that possess an iron-responsive element (IRE) in their mRNA, such as ferritin or transferrin, is regulated by binding with Fe and iron regulatory proteins (IRPs) [ 49 ]. Since the mRNA of the PrP C gene possesses an IRE, the Fe level controls its expression [ 50 ].…”

“…In addition to ZnT-1 and these amyloidogenic proteins, MT-3 and carnosine (β-alanyl histidine), which is synthesized and secreted from glial cells, may contribute to the maintenance of metal homeostasis at synapses [ 82 , 83 ]. Meanwhile, these neurometals can influence the expression of PrP and contribute the conformational conversion from PrP C to PrP Sc as described previously [ 26 , 27 , 28 , 39 , 50 , 59 ].…”