Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells

Abstract

Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the and data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear. The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several proteins, including abnormal PrP in prion disease and the Aβ oligomer in Alzheimer's disease. In the present study, melanin, a main determinant of skin color, was newly found to interact with this N-terminal region and inhibits abnormal PrP formation in prion-infected cells. However, the data for prion infection in mice lacking melanin production suggest that melanin is not associated with the prion disease mechanism, although the incidence of prion disease is reportedly much higher in white people than in black people. Thus, the roles of the PrP-melanin interaction remain to be further elucidated, but melanin might be a useful competitive tool for evaluating the functions of other ligands at the N-terminal region.

Perspective Chapter: Beyond the Chlorophyll Molecule, Are There Other Organic Compounds Capable of Dissociating the Water Molecule? New and Unexpected Insights

“…3. Melanin is the darkest substance man has ever known [26] because it absorbs any type of energy and dissipates it in a unique way: dissociating the water molecule [27].…”

Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review

“…The PrP octapeptide repeats are critical for this binding activity, given that binding becomes stronger as the number of octapeptide repeats increases, thus suggesting a potential role for PrP in the regulation of the microtubule dynamics in neurons [71]; (4) Acetylcholinesterase (AChE), a key protein in the cholinergic system both in neural and non-neural tissues, through a heterologous association, induces aggregation of monomeric PrP and modifies the structural properties of PrP amyloid fibrils. The PrP-AChE interaction occurs at two sites in the PrP N-terminal domain (residues 23–99 and 100–120) [72]; (5) Melanin, a main determinant of skin color that interacts with PrP at the N-terminal domain specifically, strongly interacts with the PrP region at amino acids 23–50 and weakly interacts with the PrP octarepeat peptide region including residues 51–90; the pathogenic role of the PrP-melanin interaction remains undefined, even if this skin pigment might be useful for evaluating the functions of other ligands at the N-terminal region [73]; and (6) Nucleic Acids, including RNA and DNA, have been shown to interact with PrP both in vitro and in vivo, indicating their involvement as molecular cofactors of PrP C conversion into PrP Sc -like species [74].…”

Extraction, physicochemical characterisation, and bioactive properties of ink melanin from cuttlefish (Sepiaesculenta)

“…The most prevalent structure of Sepia melanin by atomic force microscopy comprises aggregations of particles with diameters of 100-200 mm (Magarelli et al, 2010). Melanin extracted from animals, plants, and microorganisms shows antioxidant (Zou et al, 2015), anti-ageing (Lu et al, 2014), antimicrobial (Manivasagan et al, 2013), anti-radiation (Zhang et al, 2016), antitumor (El-Naggar & El-Ewasy, 2017), antiviral (Hamanaka et al, 2017), anti-inflammatory (Dong et al, 2017), and immunoregulatory activities (Li et al, 2018). Thus, melanin has been used in food, medicine, cosmetics, and other industries.…”