Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma

Daus, Martin L.

doi:10.3390/biology5010002

Cited by 7 publications

(7 citation statements)

References 41 publications

(46 reference statements)

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“…In the broader sense, prions also challenge the Central Dogma of Biology that information is carried in DNA and RNA [ 40 , 41 , 42 ]. Prions reveal that different biological outcomes can be encoded in protein conformations (rather than in protein primary sequence).…”

Section: Protein Functions Are Lost Reduced and Subverted Upon Prmentioning

confidence: 99%

Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology

Allison

DuVal

Nguyen-Phuoc

et al. 2017

IJMS

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Prions have served as pathfinders that reveal many aspects of proteostasis in neurons. The recent realization that several prominent neurodegenerative diseases spread via a prion-like mechanism illuminates new possibilities for diagnostics and therapeutics. Thus, key proteins in Alzheimer Disease and Amyotrophic lateral sclerosis (ALS), including amyloid-β precursor protein, Tau and superoxide dismutase 1 (SOD1), spread to adjacent cells in their misfolded aggregated forms and exhibit template-directed misfolding to induce further misfolding, disruptions to proteostasis and toxicity. Here we invert this comparison to ask what these prion-like diseases can teach us about the broad prion disease class, especially regarding the loss of these key proteins’ function(s) as they misfold and aggregate. We also consider whether functional amyloids might reveal a role for subverted protein function in neurodegenerative disease. Our synthesis identifies SOD1 as an exemplar of protein functions being lost during prion-like protein misfolding, because SOD1 is inherently unstable and loses function in its misfolded disease-associated form. This has under-appreciated parallels amongst the canonical prion diseases, wherein the normally folded prion protein, PrPC, is reduced in abundance in fatal familial insomnia patients and during the preclinical phase in animal models, apparently via proteostatic mechanisms. Thus while template-directed misfolding and infectious properties represent gain-of-function that fascinates proteostasis researchers and defines (is required for) the prion(-like) diseases, loss and subversion of the functions attributed to hallmark proteins in neurodegenerative disease needs to be integrated into design towards effective therapeutics. We propose experiments to uniquely test these ideas.

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Section: Protein Functions Are Lost Reduced and Subverted Upon Prmentioning

confidence: 99%

Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology

Allison

DuVal

Nguyen-Phuoc

et al. 2017

IJMS

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“…However, thus far, most examples of protein aggregation, polymerization and prion-like behavior occur in the context of diseases [ 42 , 43 , 44 ]. The best characterized examples of deleterious protein aggregation and prion-like behavior are found in neurodegenerative diseases [ 45 , 46 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

Confocal Spectroscopy to Study Dimerization, Oligomerization and Aggregation of Proteins: A Practical Guide

Gambin

Polinkovsky

François

et al. 2016

IJMS

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Protein self-association is a key feature that can modulate the physiological role of proteins or lead to deleterious effects when uncontrolled. Protein oligomerization is a simple way to modify the activity of a protein, as the modulation of binding interfaces allows for self-activation or inhibition, or variation in the selectivity of binding partners. As such, dimerization and higher order oligomerization is a common feature in signaling proteins, for example, and more than 70% of enzymes have the potential to self-associate. On the other hand, protein aggregation can overcome the regulatory mechanisms of the cell and can have disastrous physiological effects. This is the case in a number of neurodegenerative diseases, where proteins, due to mutation or dysregulation later in life, start polymerizing and often fibrillate, leading to the creation of protein inclusion bodies in cells. Dimerization, well-defined oligomerization and random aggregation are often difficult to differentiate and characterize experimentally. Single molecule “counting” methods are particularly well suited to the study of self-oligomerization as they allow observation and quantification of behaviors in heterogeneous conditions. However, the extreme dilution of samples often causes weak complexes to dissociate, and rare events can be overlooked. Here, we discuss a straightforward alternative where the principles of single molecule detection are used at higher protein concentrations to quantify oligomers and aggregates in a background of monomers. We propose a practical guide for the use of confocal spectroscopy to quantify protein oligomerization status and also discuss about its use in monitoring changes in protein aggregation in drug screening assays.

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“…For instance, amyloid prions are sometimes considered as conformational ("second order") templates in addition to DNA ("first order") ones. 4,101,102 This view is quite close to the bimodularity principle, but does not cover non-amyloid hereditary prions which reproduce via positive feedback loops without second order templates. The fact that prion function and evolution are affected at 2 levels (DNA and protein) has been recently pointed out by Wickner and Kelly.…”

Section: Discussionmentioning

confidence: 96%

Allelic variants of hereditary prions: The bimodularity principle

Tikhodeyev

Тарасов

Bondarev

2017

Prion

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Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either "canonical" (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as "gene" and "allele" to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor.

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Disease Transmission by Misfolded Prion-Protein Isoforms, Prion-Like Amyloids, Functional Amyloids and the Central Dogma

Cited by 7 publications

References 41 publications

Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology

Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology

Confocal Spectroscopy to Study Dimerization, Oligomerization and Aggregation of Proteins: A Practical Guide

Allelic variants of hereditary prions: The bimodularity principle

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