Alteration of Biomolecular Conformation by Aluminum-Implications for Protein Misfolding Disease.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Alzheimer Disease* ; Neurodegenerative Diseases* ; Neurotoxicity Syndromes* ; Proteostasis Deficiencies*; Aluminum/metabolism ; Animals ; Protein Conformation

The natural element aluminum possesses a number of unique biochemical and biophysical properties that make this highly neurotoxic species deleterious towards the structural integrity, conformation, reactivity and stability of several important biomolecules. These include aluminum's (i) small ionic size and highly electrophilic nature, having the highest charge density of any metallic cation with a Z ² /r of 18 (ionic charge +3, radius 0.5 nm); (ii) inclination to form extremely stable electrostatic bonds with a tendency towards covalency; (iii) ability to interact irreversibly and/or significantly slow down the exchange-rates of complex aluminum-biomolecular interactions; (iv) extremely dense electropositive charge with one of the highest known affinities for oxygen-donor ligands such as phosphate; (v) presence as the most abundant metal in the Earth's biosphere and general bioavailability in drinking water, food, medicines, consumer products, groundwater and atmospheric dust; and (vi) abundance as one of the most commonly encountered intracellular and extracellular metallotoxins. Despite aluminum's prevalence and abundance in the biosphere it is remarkably well-tolerated by all plant and animal species; no organism is known to utilize aluminum metabolically; however, a biological role for aluminum has been assigned in the compaction of chromatin. In this Communication, several examples are given where aluminum has been shown to irreversibly perturb and/or stabilize the natural conformation of biomolecules known to be important in energy metabolism, gene expression, cellular homeostasis and pathological signaling in neurological disease. Several neurodegenerative disorders that include the tauopathies, Alzheimer's disease and multiple prion disorders involve the altered conformation of naturally occurring cellular proteins. Based on the data currently available we speculate that one way aluminum contributes to neurological disease is to induce the misfolding of naturally occurring proteins into altered pathological configurations that contribute to the neurodegenerative disease process.

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AG18031 United States NH NIH HHS; R01 AG018031 United States AG NIA NIH HHS; AG038834 United States NH NIH HHS; R01 AG038834 United States AG NIA NIH HHS; 2021-2022 The Brown Foundation, Joe and Dorothy Dorsett Innovation in Science Healthy Aging Award

Keywords: Alzheimer’s disease (AD); adenosine triphosphate (ATP); aluminum; biomolecules; histone linker proteins (H1 class); prion disease (PrD); protein folding disease

CPD4NFA903 (Aluminum)

Date Created: 20220826 Date Completed: 20220829 Latest Revision: 20240516

20240516

PMC9412470

10.3390/molecules27165123

36014365