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Biomolecules
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Prion Diseases: A Model for Neurodegenerative Disorders
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Prion Diseases: A Model for Neurodegenerative Disorders

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (1 June 2020) | Viewed by 27566

Special Issue Editor

Dr. Sabine Gilch

E-Mail Website
Guest Editor
Department of Comparative Biology and Experimental Medicine,Calgary Prion Research Unit, Faculty of Veterinary Medicine and Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada
Interests: prion diseases; chronic wasting disease; prion strains; pathogenesis; vesicle trafficking; cholesterol metabolism; PrPC processing; therapy; Alzheimer’s disease

Special Issue Information

Dear Colleagues,

Prion diseases or transmissible spongiform encephalopathies are invariably fatal neurodegenerative disorders of humans and animals. They are caused by prions, self-propagating proteinaceous infectious particles which consist of a misfolded and aggregation-prone isoform of the cellular prion protein (PrPC), termed PrPSc. Over the last decade, the concept of prion-like mechanisms in other neurodegenerative diseases evolved, based on the principle of seeding, spreading, and propagation of protein misfolding in the brains of affected individuals. These mechanisms were initially ascribed to prions and now have been well established for other neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease. Still, prion diseases are exceptional as their natural transmission is well documented while not observed, for example, in Alzheimer’s or Parkinson’s disease. Despite this difference, the structural characteristics and shared mechanisms of propagation or cell-to-cell transmission suggest potential common therapeutic targets and principles of diagnostic assays, which will be discussed in this Special Issue.

Dr. Sabine Gilch
Guest Editor

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Keywords

  • prions
  • prion diseases
  • prion-like diseases
  • therapy
  • diagnosis
  • propagation
  • Alzheimer’s disease
  • Parkinsons’s disease

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Published Papers (5 papers)

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Review

48 pages, 2241 KiB  
Review
Prion-Like Propagation Mechanisms in Tauopathies and Traumatic Brain Injury: Challenges and Prospects
by Hadeel Alyenbaawi, W. Ted Allison and Sue-Ann Mok
Biomolecules 2020, 10(11), 1487; https://doi.org/10.3390/biom10111487 - 27 Oct 2020
Cited by 10 | Viewed by 4489
Abstract
The accumulation of tau protein in the form of filamentous aggregates is a hallmark of many neurodegenerative diseases such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). These dementias share traumatic brain injury (TBI) as a prominent risk factor. Tau aggregates can [...] Read more.
The accumulation of tau protein in the form of filamentous aggregates is a hallmark of many neurodegenerative diseases such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). These dementias share traumatic brain injury (TBI) as a prominent risk factor. Tau aggregates can transfer between cells and tissues in a “prion-like” manner, where they initiate the templated misfolding of normal tau molecules. This enables the spread of tau pathology to distinct parts of the brain. The evidence that tauopathies spread via prion-like mechanisms is considerable, but work detailing the mechanisms of spread has mostly used in vitro platforms that cannot fully reveal the tissue-level vectors or etiology of progression. We review these issues and then briefly use TBI and CTE as a case study to illustrate aspects of tauopathy that warrant further attention in vivo. These include seizures and sleep/wake disturbances, emphasizing the urgent need for improved animal models. Dissecting these mechanisms of tauopathy progression continues to provide fresh inspiration for the design of diagnostic and therapeutic approaches. Full article
(This article belongs to the Special Issue Prion Diseases: A Model for Neurodegenerative Disorders)
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20 pages, 884 KiB  
Review
From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins
by Cristóbal Marrero-Winkens, Charu Sankaran and Hermann M. Schätzl
Biomolecules 2020, 10(9), 1305; https://doi.org/10.3390/biom10091305 - 10 Sep 2020
Cited by 12 | Viewed by 6024
Abstract
Many devastating neurodegenerative diseases are driven by the misfolding of normal proteins into a pathogenic abnormal conformation. Examples of such protein misfolding diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. The misfolded proteins involved in these diseases [...] Read more.
Many devastating neurodegenerative diseases are driven by the misfolding of normal proteins into a pathogenic abnormal conformation. Examples of such protein misfolding diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. The misfolded proteins involved in these diseases form self-templating oligomeric assemblies that recruit further correctly folded protein and induce their conversion. Over time, this leads to the formation of high molecular and mostly fibrillar aggregates that are increasingly inefficient at converting normal protein. Evidence from a multitude of in vitro models suggests that fibrils are fragmented to form new seeds, which can convert further normal protein and also spread to neighboring cells as observed in vivo. While fragmentation and seed generation were suggested as crucial steps in aggregate formation decades ago, the biological pathways involved remain largely unknown. Here, we show that mechanisms of aggregate clearance—namely the mammalian Hsp70–Hsp40–Hsp110 tri-chaperone system, macro-autophagy, and the proteasome system—may not only be protective, but also play a role in fragmentation. We further review the challenges that exist in determining the precise contribution of these mechanisms to protein misfolding diseases and suggest future directions to resolve these issues. Full article
(This article belongs to the Special Issue Prion Diseases: A Model for Neurodegenerative Disorders)
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19 pages, 1540 KiB  
Review
Defining the Protein Seeds of Neurodegeneration using Real-Time Quaking-Induced Conversion Assays
by Matteo Manca and Allison Kraus
Biomolecules 2020, 10(9), 1233; https://doi.org/10.3390/biom10091233 - 25 Aug 2020
Cited by 7 | Viewed by 4937
Abstract
Neurodegenerative diseases are characterized by the accumulation of disease-related misfolded proteins. It is now widely understood that the characteristic self-amplifying (i.e., seeding) capacity once only attributed to the prions of transmissible spongiform encephalopathy diseases is a feature of other misfolded proteins of neurodegenerative [...] Read more.
Neurodegenerative diseases are characterized by the accumulation of disease-related misfolded proteins. It is now widely understood that the characteristic self-amplifying (i.e., seeding) capacity once only attributed to the prions of transmissible spongiform encephalopathy diseases is a feature of other misfolded proteins of neurodegenerative diseases, including tau, Aβ, and αSynuclein (αSyn). Ultrasensitive diagnostic assays, known as real-time quaking-induced conversion (RT-QuIC) assays, exploit these seeding capabilities in order to exponentially amplify protein seeds from various biospecimens. To date, RT-QuIC assays have been developed for the detection of protein seeds related to known prion diseases of mammals, the αSyn aggregates of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, and the tau aggregates of Alzheimer’s disease, chronic traumatic encephalopathy, and other tauopathies including progressive supranuclear palsy. Application of these assays to premortem human biospecimens shows promise for diagnosis of neurodegenerative disease and is an area of active investigation. RT-QuIC assays are also powerful experimental tools that can be used to dissect seeding networks within and between tissues and to evaluate how protein seed distribution and quantity correlate to disease-related outcomes in a host. As well, RT-QuIC application may help characterize molecular pathways influencing protein seed accumulation, transmission, and clearance. In this review we discuss the application of RT-QuIC assays as diagnostic, experimental, and structural tools for detection and discrimination of PrP prions, tau, and αSyn protein seeds. Full article
(This article belongs to the Special Issue Prion Diseases: A Model for Neurodegenerative Disorders)
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Graphical abstract

23 pages, 1402 KiB  
Review
C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins
by Carl Alexander Sandhof, Simon Oliver Hoppe, Jessica Tittelmeier and Carmen Nussbaum-Krammer
Biomolecules 2020, 10(8), 1188; https://doi.org/10.3390/biom10081188 - 15 Aug 2020
Cited by 8 | Viewed by 4760
Abstract
A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites [...] Read more.
A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients. Full article
(This article belongs to the Special Issue Prion Diseases: A Model for Neurodegenerative Disorders)
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24 pages, 1666 KiB  
Review
POSCAbilities: The Application of the Prion Organotypic Slice Culture Assay to Neurodegenerative Disease Research
by Hailey Pineau and Valerie Sim
Biomolecules 2020, 10(7), 1079; https://doi.org/10.3390/biom10071079 - 20 Jul 2020
Cited by 12 | Viewed by 6194
Abstract
Prion diseases are fatal, transmissible neurodegenerative disorders whose pathogenesis is driven by the misfolding, self-templating and cell-to-cell spread of the prion protein. Other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, share some of these prion-like features, [...] Read more.
Prion diseases are fatal, transmissible neurodegenerative disorders whose pathogenesis is driven by the misfolding, self-templating and cell-to-cell spread of the prion protein. Other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, share some of these prion-like features, with different aggregation-prone proteins. Consequently, researchers have begun to apply prion-specific techniques, like the prion organotypic slice culture assay (POSCA), to these disorders. In this review we explore the ways in which the prion phenomenon has been used in organotypic cultures to study neurodegenerative diseases from the perspective of protein aggregation and spreading, strain propagation, the role of glia in pathogenesis, and efficacy of drug treatments. We also present an overview of the advantages and disadvantages of this culture system compared to in vivo and in vitro models and provide suggestions for new directions. Full article
(This article belongs to the Special Issue Prion Diseases: A Model for Neurodegenerative Disorders)
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