Next Article in Journal
A Mini-Review on the Effect of Docosahexaenoic Acid (DHA) on Cerulein-Induced and Hypertriglyceridemic Acute Pancreatitis
Previous Article in Journal
Zinc Signals and Immunity
Previous Article in Special Issue
Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases
Article Menu
Issue 10 (October) cover image

Export Article

Open AccessReview
Int. J. Mol. Sci. 2017, 18(10), 2223; https://doi.org/10.3390/ijms18102223

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

1
Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, AB T6G 2M8, Canada
2
Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
3
Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2M8, Canada
*
Author to whom correspondence should be addressed.
Received: 10 July 2017 / Revised: 18 October 2017 / Accepted: 20 October 2017 / Published: 24 October 2017
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
View Full-Text   |   Download PDF [4198 KB, uploaded 24 October 2017]   |  

Abstract

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. View Full-Text
Keywords: protein homeostasis; prion-like disease; amyotrophic lateral sclerosis; functional amyloid; scrapie; premelanosome protein (PMEL17); strains; SOD1 protein homeostasis; prion-like disease; amyotrophic lateral sclerosis; functional amyloid; scrapie; premelanosome protein (PMEL17); strains; SOD1
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Allison, W.T.; DuVal, M.G.; Nguyen-Phuoc, K.; Leighton, P.L.A. Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology. Int. J. Mol. Sci. 2017, 18, 2223.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top