Iron-responsive-like elements and neurodegenerative ferroptosis.

Area of Science:

• Neurobiology
• RNA Biology
• Neurodegenerative Disease Research

Background:

• Neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), Parkinson's disease dementia (PDD), and Lewy body dementia (LDD), are linked to disrupted iron homeostasis in specific brain regions.
• Misfolded proteins like amyloid-beta (from amyloid precursor protein - APP), alpha-synuclein, and prion protein (PrP) form neuropathic inclusions, and their transcripts contain iron-responsive-like element (IRE-like) RNA stem-loops.

Purpose of the Study:

• To explore the role of common-acting iron-responsive 5' untranslated region (5'UTR) motifs in the pathogenesis of cognitive decline associated with AD, PD, PDD, and LDD.
• To identify IRE-like RNA motifs in APP, alpha-synuclein, and PrP transcripts as potential therapeutic drug targets.

Main Methods:

• Analysis of RNA stem-loop structures in 5'UTRs of key proteins involved in neurodegeneration.
• Investigating the link between iron homeostasis, IRE-like elements, and neuronal ferroptosis.
• Reviewing the translational control mechanisms of iron metabolism, including ferritin and APP.

Main Results:

• Common IRE-like RNA stem-loop motifs in the 5'UTRs of APP, alpha-synuclein, and PrP transcripts are significant in the biology of cognitive decline.
• Excess brain iron can activate these IRE-like sequences, potentially accelerating neuronal ferroptosis, cognitive deficits, and amyloidosis.
• APP and alpha-synuclein play roles in iron transport, with gene duplications linked to familial AD and PDD.

Conclusions:

• IRE-like RNA motifs in APP, alpha-synuclein, and PrP mRNAs represent druggable targets for therapies aimed at preventing iron dysregulation and subsequent cognitive decline in neurodegenerative diseases.
• Therapeutic strategies could involve inhibiting alpha-synuclein translation to mitigate manganese toxicity and associated cognitive issues, and potentially activating APP and ferritin while inhibiting alpha-synuclein translation for heavy metal toxicity pathologies impacting iron export.