International Journal of Molecular Sciences

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12 pages, 2391 KiB

Open AccessArticle

Dangerous Stops: Nonsense Mutations Can Dramatically Increase Frequency of Prion Conversion

by Alexander A. Dergalev, Valery N. Urakov, Michael O. Agaphonov, Alexander I. Alexandrov and Vitaly V. Kushnirov

Int. J. Mol. Sci. 2021, 22(4), 1542; https://doi.org/10.3390/ijms22041542 - 3 Feb 2021

Cited by 2 | Viewed by 1960

Abstract

Amyloid formation is associated with many incurable diseases. For some of these, sporadic cases are much more common than familial ones. Some reports point to the role of somatic cell mosaicism in these cases via origination of amyloids in a limited number of [...] Read more.

Amyloid formation is associated with many incurable diseases. For some of these, sporadic cases are much more common than familial ones. Some reports point to the role of somatic cell mosaicism in these cases via origination of amyloids in a limited number of cells, which can then spread through tissues. However, specific types of sporadic mutations responsible for such effects are unknown. In order to identify mutations capable of increasing the de novo appearance of amyloids, we searched for such mutants in the yeast prionogenic protein Sup35. We introduced to yeast cells an additional copy of the SUP35 gene with mutated amyloidogenic domain and observed that some nonsense mutations increased the incidence of prions by several orders of magnitude. This effect was related to exposure at the C-terminus of an internal amyloidogenic region of Sup35. We also discovered that SUP35 mRNA could undergo splicing, although inefficiently, causing appearance of a shortened Sup35 isoform lacking its functional domain, which was also highly prionogenic. Our data suggest that truncated forms of amyloidogenic proteins, resulting from nonsense mutations or alternative splicing in rare somatic cells, might initiate spontaneous localized formation of amyloids, which can then spread, resulting in sporadic amyloid disease. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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18 pages, 3169 KiB

Open AccessArticle

Effects of Alzheimer-Like Pathology on Homocysteine and Homocysteic Acid Levels—An Exploratory In Vivo Kinetic Study

by Hendrik Nieraad, Natasja de Bruin, Olga Arne, Martine C. J. Hofmann, Robert Gurke, Dominik Schmidt, Marcel Ritter, Michael J. Parnham and Gerd Geisslinger

Int. J. Mol. Sci. 2021, 22(2), 927; https://doi.org/10.3390/ijms22020927 - 18 Jan 2021

Cited by 6 | Viewed by 2219

Abstract

Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer’s disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this [...] Read more.

Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer’s disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of App^NL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic App^NL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the App^NL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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23 pages, 7126 KiB

Open AccessArticle

Nonsense Mutations in the Yeast SUP35 Gene Affect the [PSI⁺] Prion Propagation

by Nina P. Trubitsina, Olga M. Zemlyanko, Stanislav A. Bondarev and Galina A. Zhouravleva

Int. J. Mol. Sci. 2020, 21(5), 1648; https://doi.org/10.3390/ijms21051648 - 28 Feb 2020

Cited by 3 | Viewed by 3183

Abstract

The essential SUP35 gene encodes yeast translation termination factor eRF3. Previously, we isolated nonsense mutations sup35-n and proposed that the viability of such mutants can be explained by readthrough of the premature stop codon. Such mutations, as well as the prion [PSI [...] Read more.

The essential SUP35 gene encodes yeast translation termination factor eRF3. Previously, we isolated nonsense mutations sup35-n and proposed that the viability of such mutants can be explained by readthrough of the premature stop codon. Such mutations, as well as the prion [PSI⁺], can appear in natural yeast populations, and their combinations may have different effects on the cells. Here, we analyze the effects of the compatibility of sup35-n mutations with the [PSI⁺] prion in haploid and diploid cells. We demonstrated that sup35-n mutations are incompatible with the [PSI⁺] prion, leading to lethality of sup35-n [PSI⁺] haploid cells. In diploid cells the compatibility of [PSI⁺] with sup35-n depends on how the corresponding diploid was obtained. Nonsense mutations sup35-21, sup35-74, and sup35-218 are compatible with the [PSI⁺] prion in diploid strains, but affect [PSI⁺] properties and lead to the formation of new prion variant. The only mutation that could replace the SUP35 wild-type allele in both haploid and diploid [PSI⁺] strains, sup35-240, led to the prion loss. Possibly, short Sup35_1–55 protein, produced from the sup35-240 allele, is included in Sup35 aggregates and destabilize them. Alternatively, single molecules of Sup35_1–55 can stick to aggregate ends, and thus interrupt the fibril growth. Thus, we can conclude that sup35-240 mutation prevents [PSI⁺] propagation and can be considered as a new pnm mutation. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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14 pages, 1760 KiB

Open AccessArticle

A Capped Peptide of the Aggregation Prone NAC 71–82 Amino Acid Stretch of α-Synuclein Folds into Soluble β-Sheet Oligomers at Low and Elevated Peptide Concentrations

by Thomas Näsström, Jörgen Ådén, Fumina Shibata, Per Ola Andersson and Björn C.G. Karlsson

Int. J. Mol. Sci. 2020, 21(5), 1629; https://doi.org/10.3390/ijms21051629 - 27 Feb 2020

Cited by 7 | Viewed by 3539

Abstract

Although Lewy bodies and Lewy neurites are hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), misfolded α-synuclein oligomers are nowadays believed to be key for the development of these diseases. Attempts to target soluble misfolded species of the full-length protein [...] Read more.

Although Lewy bodies and Lewy neurites are hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), misfolded α-synuclein oligomers are nowadays believed to be key for the development of these diseases. Attempts to target soluble misfolded species of the full-length protein have been limited so far, probably due to the fast aggregation kinetics and burial of aggregation prone segments in final cross-β-sheet fibrils. A previous characterisation study of fibrils prepared from a capped peptide of the non-amyloid β-component (NAC) 71–82 amino acid stretch of α-synuclein demonstrated an increased aggregation propensity resulting in a cross-β-structure that is also found in prion proteins. From this, it was suggested that capped NAC 71–82 peptide oligomers would provide interesting motifs with a capacity to regulate disease development. Here, we demonstrated, from a series of circular dichroism spectroscopic measurements and molecular dynamics simulations, the molecular-environment-sensitive behaviour of the capped NAC 71–82 peptide in a solution phase and the formation of β-sheet oligomeric structures in the supernatant of a fibrillisation mixture. These results highlighted the use of the capped NAC 71–82 peptide as a motif in the preparation of oligomeric β-sheet structures that potentially could be used in therapeutic strategies in the fight against progressive neurodegenerative disorders, such as PD and DLB. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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Review

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19 pages, 1176 KiB

Open AccessReview

From Prions to Stress Granules: Defining the Compositional Features of Prion-Like Domains That Promote Different Types of Assemblies

by Anastasia Fomicheva and Eric D. Ross

Int. J. Mol. Sci. 2021, 22(3), 1251; https://doi.org/10.3390/ijms22031251 - 27 Jan 2021

Cited by 20 | Viewed by 4982

Abstract

Stress granules are ribonucleoprotein assemblies that form in response to cellular stress. Many of the RNA-binding proteins found in stress granule proteomes contain prion-like domains (PrLDs), which are low-complexity sequences that compositionally resemble yeast prion domains. Mutations in some of these PrLDs have [...] Read more.

Stress granules are ribonucleoprotein assemblies that form in response to cellular stress. Many of the RNA-binding proteins found in stress granule proteomes contain prion-like domains (PrLDs), which are low-complexity sequences that compositionally resemble yeast prion domains. Mutations in some of these PrLDs have been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia, and are associated with persistent stress granule accumulation. While both stress granules and prions are macromolecular assemblies, they differ in both their physical properties and complexity. Prion aggregates are highly stable homopolymeric solids, while stress granules are complex dynamic biomolecular condensates driven by multivalent homotypic and heterotypic interactions. Here, we use stress granules and yeast prions as a paradigm to examine how distinct sequence and compositional features of PrLDs contribute to different types of PrLD-containing assemblies. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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15 pages, 1715 KiB

Open AccessReview

Neurodegenerative Proteinopathies in the Proteoform Spectrum—Tools and Challenges

by Aneeqa Noor, Saima Zafar and Inga Zerr

Int. J. Mol. Sci. 2021, 22(3), 1085; https://doi.org/10.3390/ijms22031085 - 22 Jan 2021

Cited by 8 | Viewed by 3663

Abstract

Proteinopathy refers to a group of disorders defined by depositions of amyloids within living tissue. Neurodegenerative proteinopathies, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt–Jakob disease, and others, constitute a large fraction of these disorders. Amyloids are highly insoluble, ordered, stable, beta-sheet rich proteins. The [...] Read more.

Proteinopathy refers to a group of disorders defined by depositions of amyloids within living tissue. Neurodegenerative proteinopathies, including Alzheimer’s disease, Parkinson’s disease, Creutzfeldt–Jakob disease, and others, constitute a large fraction of these disorders. Amyloids are highly insoluble, ordered, stable, beta-sheet rich proteins. The emerging theory about the pathophysiology of neurodegenerative proteinopathies suggests that the primary amyloid-forming proteins, also known as the prion-like proteins, may exist as multiple proteoforms that contribute differentially towards the disease prognosis. It is therefore necessary to resolve these disorders on the level of proteoforms rather than the proteome. The transient and hydrophobic nature of amyloid-forming proteins and the minor post-translational alterations that lead to the formation of proteoforms require the use of highly sensitive and specialized techniques. Several conventional techniques, like gel electrophoresis and conventional mass spectrometry, have been modified to accommodate the proteoform theory and prion-like proteins. Several new ones, like imaging mass spectrometry, have also emerged. This review aims to discuss the proteoform theory of neurodegenerative disorders along with the utility of these proteomic techniques for the study of highly insoluble proteins and their associated proteoforms. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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12 pages, 1665 KiB

Open AccessReview

From Posttranslational Modifications to Disease Phenotype: A Substrate Selection Hypothesis in Neurodegenerative Diseases

by Ilia V. Baskakov

Int. J. Mol. Sci. 2021, 22(2), 901; https://doi.org/10.3390/ijms22020901 - 18 Jan 2021

Cited by 7 | Viewed by 2598

Abstract

A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to [...] Read more.

A number of neurodegenerative diseases including prion diseases, tauopathies and synucleinopathies exhibit multiple clinical phenotypes. A diversity of clinical phenotypes has been attributed to the ability of amyloidogenic proteins associated with a particular disease to acquire multiple, conformationally distinct, self-replicating states referred to as strains. Structural diversity of strains formed by tau, α-synuclein or prion proteins has been well documented. However, the question how different strains formed by the same protein elicit different clinical phenotypes remains poorly understood. The current article reviews emerging evidence suggesting that posttranslational modifications are important players in defining strain-specific structures and disease phenotypes. This article put forward a new hypothesis referred to as substrate selection hypothesis, according to which individual strains selectively recruit protein isoforms with a subset of posttranslational modifications that fit into strain-specific structures. Moreover, it is proposed that as a result of selective recruitment, strain-specific patterns of posttranslational modifications are formed, giving rise to unique disease phenotypes. Future studies should define whether cell-, region- and age-specific differences in metabolism of posttranslational modifications play a causative role in dictating strain identity and structural diversity of strains of sporadic origin. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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15 pages, 5047 KiB

Open AccessReview

Mechanisms for Curing Yeast Prions

by Lois E. Greene, Farrin Saba, Rebecca E. Silberman and Xiaohong Zhao

Int. J. Mol. Sci. 2020, 21(18), 6536; https://doi.org/10.3390/ijms21186536 - 7 Sep 2020

Cited by 11 | Viewed by 2560

Abstract

Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is typically rich in β-sheet, serves as a template to convert the prion protein into its misfolded conformation. In yeast, the misfolded [...] Read more.

Prions are infectious proteins that self-propagate by changing from their normal folded conformation to a misfolded conformation. The misfolded conformation, which is typically rich in β-sheet, serves as a template to convert the prion protein into its misfolded conformation. In yeast, the misfolded prion proteins are assembled into amyloid fibers or seeds, which are constantly severed and transmitted to daughter cells. To cure prions in yeast, it is necessary to eliminate all the prion seeds. Multiple mechanisms of curing have been found including inhibiting severing of the prion seeds, gradual dissolution of the prion seeds, asymmetric segregation of the prion seeds between mother and daughter cells during cell division, and degradation of the prion seeds. These mechanisms, achieved by using different protein quality control machinery, are not mutually exclusive; depending on conditions, multiple mechanisms may work simultaneously to achieve curing. This review discusses the various methods that have been used to differentiate between these mechanisms of curing. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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17 pages, 891 KiB

Open AccessReview

How Do Yeast Cells Contend with Prions?

by Reed B. Wickner, Herman K. Edskes, Moonil Son, Songsong Wu and Madaleine Niznikiewicz

Int. J. Mol. Sci. 2020, 21(13), 4742; https://doi.org/10.3390/ijms21134742 - 3 Jul 2020

Cited by 8 | Viewed by 4003

Abstract

Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In Saccharomyces cerevisiae, at least [...] Read more.

Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In Saccharomyces cerevisiae, at least eight anti-prion systems deal with pathogenic amyloid yeast prions by (1) blocking their generation (Ssb1,2, Ssz1, Zuo1), (2) curing most variants as they arise (Btn2, Cur1, Hsp104, Upf1,2,3, Siw14), and (3) limiting the pathogenicity of variants that do arise and propagate (Sis1, Lug1). Known mechanisms include facilitating proper folding of the prion protein (Ssb1,2, Ssz1, Zuo1), producing highly asymmetric segregation of prion filaments in mitosis (Btn2, Hsp104), competing with the amyloid filaments for prion protein monomers (Upf1,2,3), and regulation of levels of inositol polyphosphates (Siw14). It is hoped that the discovery of yeast anti-prion systems and elucidation of their mechanisms will facilitate finding analogous or homologous systems in humans, whose manipulation may be useful in treatment. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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30 pages, 3771 KiB

Open AccessReview

Connecting RNA-Modifying Similarities of TDP-43, FUS, and SOD1 with MicroRNA Dysregulation Amidst A Renewed Network Perspective of Amyotrophic Lateral Sclerosis Proteinopathy

by Jade Pham, Matt Keon, Samuel Brennan and Nitin Saksena

Int. J. Mol. Sci. 2020, 21(10), 3464; https://doi.org/10.3390/ijms21103464 - 14 May 2020

Cited by 20 | Viewed by 6784

Abstract

Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly [...] Read more.

Beyond traditional approaches in understanding amyotrophic lateral sclerosis (ALS), multiple recent studies in RNA-binding proteins (RBPs)—including transactive response DNA-binding protein (TDP-43) and fused in sarcoma (FUS)—have instigated an interest in their function and prion-like properties. Given their prominence as hallmarks of a highly heterogeneous disease, this prompts a re-examination of the specific functional interrelationships between these proteins, especially as pathological SOD1—a non-RBP commonly associated with familial ALS (fALS)—exhibits similar properties to these RBPs including potential RNA-regulatory capabilities. Moreover, the cytoplasmic mislocalization, aggregation, and co-aggregation of TDP-43, FUS, and SOD1 can be identified as proteinopathies akin to other neurodegenerative diseases (NDs), eliciting strong ties to disrupted RNA splicing, transport, and stability. In recent years, microRNAs (miRNAs) have also been increasingly implicated in the disease, and are of greater significance as they are the master regulators of RNA metabolism in disease pathology. However, little is known about the role of these proteins and how they are regulated by miRNA, which would provide mechanistic insights into ALS pathogenesis. This review seeks to discuss current developments across TDP-43, FUS, and SOD1 to build a detailed snapshot of the network pathophysiology underlying ALS while aiming to highlight possible novel therapeutic targets to guide future research. Full article

(This article belongs to the Special Issue Amyloids, Prions and Related Phenomena)

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