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Differential Toxicity of Antibodies to the Prion Protein.

ABSTRACT: Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profoundly neurotoxic, yet antibody ICSM18, with an epitope that overlaps with POM1, was reported to be innocuous when injected into mouse brains. In order to clarify this confusing situation, we assessed the neurotoxicity of antibodies D13 and ICSM18 with dose-escalation studies using diffusion-weighted magnetic resonance imaging and various histological techniques. We report that both D13 and ICSM18 induce rapid, dose-dependent, on-target neurotoxicity. We conclude that antibodies directed to this region may not be suitable as therapeutics. No such toxicity was found when antibodies against the flexible tail of PrPC were administered. Any attempt at immunotherapy or immunoprophylaxis of prion diseases should account for these potential untoward effects.

SUBMITTER: Reimann RR

PROVIDER: S-EPMC4731068 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Differential Toxicity of Antibodies to the Prion Protein.

Reimann Regina R RR Sonati Tiziana T Hornemann Simone S Herrmann Uli S US Arand Michael M Hawke Simon S Aguzzi Adriano A

PLoS pathogens 20160128 1

Antibodies against the prion protein PrPC can antagonize prion replication and neuroinvasion, and therefore hold promise as possible therapeutics against prion diseases. However, the safety profile of such antibodies is controversial. It was originally reported that the monoclonal antibody D13 exhibits strong target-related toxicity, yet a subsequent study contradicted these findings. We have reported that several antibodies against certain epitopes of PrPC, including antibody POM1, are profound ...[more]

PMID: 26821311

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Project description:Simple Summary DnaJB6 is a human cellular protein quality control factor that prevents diverse peptides from forming disease-associated amyloid, a highly ordered fibrous protein aggregate. DnaJB6 protects human cells, animals and yeast from toxicity caused by amyloids composed of Huntington’s-related polyglutamine, Parkinson’s-related α-synuclein, and ALS- associated TDP-43, and it cures yeast of endogenous prions (infectious amyloids). However, structurally different amyloids of one and the same prion protein, and prions composed of them, can be insensitive to anti-amyloid activity of DnaJB6. This limitation raises concerns about developing DnaJB6 as a therapeutic for amyloid diseases. Prions showing this insensitivity are highly toxic to yeast with reduced function of Sis1, a yeast protein related to DnaJB6. To begin assessing how DnaJB6 might act on amyloid in cells we tested if DnaJB6 could protect yeast from this toxicity. Although it does not eliminate the prion, it protects cells from prion toxicity, but differently than Sis1. Our work provides insight into how human DnaJB6 counteracts cellular toxicity caused by amyloid and establishes an in vivo genetic system useful for studying DnaJB6-amyloid interactions to decipher its mechanisms of action. Abstract Human J-domain protein (JDP) DnaJB6 has a broad and potent activity that prevents formation of amyloid by polypeptides such as polyglutamine, A-beta, and alpha-synuclein, related to Huntington’s, Alzheimer’s, and Parkinson’s diseases, respectively. In yeast, amyloid-based [PSI+] prions, which rely on the related JDP Sis1 for replication, have a latent toxicity that is exposed by reducing Sis1 function. Anti-amyloid activity of DnaJB6 is very effective against weak [PSI+] prions and the Sup35 amyloid that composes them, but ineffective against strong [PSI+] prions composed of structurally different amyloid of the same Sup35. This difference reveals limitations of DnaJB6 that have implications regarding its therapeutic use for amyloid disease. Here, we find that when Sis1 function is reduced, DnaJB6 represses toxicity of strong [PSI+] prions and inhibits their propagation. Both Sis1 and DnaJB6, which are regulators of protein chaperone Hsp70, counteract the toxicity by reducing excessive incorporation of the essential Sup35 into prion aggregates. However, while Sis1 apparently requires interaction with Hsp70 to detoxify [PSI+], DnaJB6 counteracts prion toxicity by a different, Hsp70-independent mechanism.

Dataset Information

Differential Toxicity of Antibodies to the Prion Protein.

Publications

Differential Toxicity of Antibodies to the Prion Protein.

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