Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection - PubMed (original) (raw)

Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection

Richard Lathe et al. J Alzheimers Dis Rep. 2017.

Abstract

The prion protein PRNP has been centrally implicated in the transmissible spongiform encephalopathies (TSEs), but its normal physiological role remains obscure. We highlight emerging evidence that PRNP displays antimicrobial activity, inhibiting the replication of multiple viruses, and also interacts directly with Alzheimer's disease (AD) amyloid-β (Aβ) peptide whose own antimicrobial role is now increasingly secure. PRNP and Aβ share share membrane-penetrating, nucleic acid binding, and antiviral properties with classical antimicrobial peptides such as LL-37. We discuss findings that binding of abnormal nucleic acids to PRNP leads to oligomerization of the protein, and suggest that this may be an entrapment and sequestration process that contributes to its antimicrobial activity. Some antimicrobial peptides are known to be exploited by infectious agents, and we cover evidence that PRNP is usurped by herpes simplex virus (HSV-1) that has evolved a virus-encoded 'anti-PRNP'.unction. These findings suggest that PRNP, like LL-37 and Aβ, is likely to be a component of the innate immune system, with implications for the pathoetiology of both AD and TSE.

Keywords: Alzheimer’s disease; PRNP; amyloid-β peptide; herpes simplex; innate immunity; spongiform encephalopathy.

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Figures

Fig.1

Fig.1

Domains of Human PRNP Protein. The graph plots the charge of the mature protein (residues 23–253) analyzed with EMBOSS (

http://www.bioinformatics.nl/cgi-bin/emboss/charge

; windowsize = 20). Grey, basic regions. Abbreviations: Aβ, binding sites for Aβ peptide; FPR, formyl peptide receptor binding site; α-HR, α-helical region; IDR, intrinsically disordered region; R, octapeptide repeats; SS, signal sequence.

Fig.2

Fig.2

Antimicrobial Activities of PRNP. In addition to the listed categories, other mechanisms are likely to include the generation of reactive oxygen species, and binding to immunomodulatory molecules including APOE and formyl peptide receptors is likely to direct the recruitment of other actors in innate immunity. Direct binding to Aβ (not depicted) and potential interactions with other antimicrobial peptides that bind to Aβ (e.g., LL-37, α-synuclein) add a further dimension. Abbreviation: HSV, herpes simplex virus type 1.

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