Beyond Amyloid Fibers: Accumulation, Biological Relevance, and Regulation of Higher-Order Prion Architectures

Naeimi, Wesley R.; Serio, Tricia R.

doi:10.3390/v14081635

Cited by 5 publications

(4 citation statements)

References 137 publications

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“…It has been suggested that excess Hsp104 results in aggregate stability (Ness et al, 2017). Conversely, Hsp104 overexpression could unbalance the proper co-chaperone stoichiometric ratio required to form functional Hsp104/70/40 complexes, thereby decreasing fragmentation necessary for prion propagation (Winkler et al, 2012;Naeimi and Serio, 2022). We show that TTR aggregates sediment in higher molecular weight fractions occasionally with Hsp104 OE (Figure 3A) and consistently with Hsp104 A503S (Figure 4C).…”

Section: The Formation Of the Ttr Aggregate And The Role Of Hsp104mentioning

confidence: 63%

The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation

Knier

Davis

Buchholz

et al. 2022

Front. Mol. Neurosci.

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Patients with the fatal disorder Transthyretin Amyloidosis (ATTR) experience polyneuropathy through the progressive destruction of peripheral nervous tissue. In these patients, the transthyretin (TTR) protein dissociates from its functional tetrameric structure, misfolds, and aggregates into extracellular amyloid deposits that are associated with disease progression. These aggregates form large fibrillar structures as well as shorter oligomeric aggregates that are suspected to be cytotoxic. Several studies have shown that these extracellular TTR aggregates enter the cell and accumulate intracellularly, which is associated with increased proteostasis response. However, there are limited experimental models to study how proteostasis influences internalized TTR aggregates. Here, we use a humanized yeast system to recapitulate intracellular TTR aggregating protein in vivo. The yeast molecular chaperone Hsp104 is a disaggregase that has been shown to fragment amyloidogenic aggregates associated with certain yeast prions and reduce protein aggregation associated with human neurogenerative diseases. In yeast, we found that TTR forms both SDS-resistant oligomers and SDS-sensitive large molecular weight complexes. In actively dividing cultures, Hsp104 has no impact on oligomeric or large aggregate populations, yet overexpression of Hsp104 is loosely associated with an increase in overall aggregate size. Interestingly, a potentiating mutation in the middle domain of Hsp104 consistently results in an increase in overall TTR aggregate size. These data suggest a novel approach to aggregate management, where the Hsp104 variant shifts aggregate populations away from toxic oligomeric species to more inert larger aggregates. In aged cultures Hsp104 overexpression has no impact on TTR aggregation profiles suggesting that these chaperone approaches to shift aggregate populations are not effective with age, possibly due to proteostasis decline.

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Section: The Formation Of the Ttr Aggregate And The Role Of Hsp104mentioning

confidence: 63%

The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation

Knier

Davis

Buchholz

et al. 2022

Front. Mol. Neurosci.

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“…PrDs of humans, also known as transmissible spongiform encephalopathies or TSEs, represent an expanding spectrum of progressive and ultimately lethal neurodegenerative disorders that globally affect about one person out of every one million per year [ 17 , 20 , 49 ]. About 85–90% of all PrDs manifest as the Creutzfeldt–Jakob disease (CJD) or a variant of the CJD (vCJD), with the remainder consisting mainly of the Gerstmann–Straussler–Scheinker (GSS) syndrome, fatal familial insomnia (FFI), variably protease-sensitive prionopathy (vPSPr), and kuru ( ; ; last accessed on 30 August 2022).…”

Section: Prion Disease (Prd) and Prion Neurobiologymentioning

confidence: 99%

“…More importantly, all microbial infections of the brain and CNS contribute to the development of a microbial- and/or viral-induced cytokine storm , which is associated with a progressive inflammatory degeneration of brain cells and tissues. The continuing progression of this cytokine storm is often accompanied by the appearance of amyloid-beta (Aβ) peptides, Aβ amyloid fibers, prion amyloids, related amyloidogenic, lipoprotein or Aβ peptide aggregation processes, the appearance of twisted neurofilamentous structures, including neurofibrillary tangles, pro-inflammatory biomarkers, gliosis of microglial cells, the formation of vacuoles and spongiform change within brain cells, neuronal cell loss, or any combination of these pathological biomarkers associated with a diverse range of human neurological disorders and phenotypic states [ 4 , 7 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Invasion and Pathological Links to Prion Disease

et al. 2022

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 disease, is a highly infectious and transmissible viral pathogen that continues to impact human health globally. Nearly ~600 million people have been infected with SARS-CoV-2, and about half exhibit some degree of continuing health complication, generically referred to as long COVID. Lingering and often serious neurological problems for patients in the post-COVID-19 recovery period include brain fog, behavioral changes, confusion, delirium, deficits in intellect, cognition and memory issues, loss of balance and coordination, problems with vision, visual processing and hallucinations, encephalopathy, encephalitis, neurovascular or cerebrovascular insufficiency, and/or impaired consciousness. Depending upon the patient’s age at the onset of COVID-19 and other factors, up to ~35% of all elderly COVID-19 patients develop a mild-to-severe encephalopathy due to complications arising from a SARS-CoV-2-induced cytokine storm and a surge in cytokine-mediated pro-inflammatory and immune signaling. In fact, this cytokine storm syndrome: (i) appears to predispose aged COVID-19 patients to the development of other neurological complications, especially those who have experienced a more serious grade of COVID-19 infection; (ii) lies along highly interactive and pathological pathways involving SARS-CoV-2 infection that promotes the parallel development and/or intensification of progressive and often lethal neurological conditions, and (iii) is strongly associated with the symptomology, onset, and development of human prion disease (PrD) and other insidious and incurable neurological syndromes. This commentary paper will evaluate some recent peer-reviewed studies in this intriguing area of human SARS-CoV-2-associated neuropathology and will assess how chronic, viral-mediated changes to the brain and CNS contribute to cognitive decline in PrD and other progressive, age-related neurodegenerative disorders.

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“…An important aspect of yeast biology is the existence of yeast prions—self-perpetuating protein aggregates that confer changes to the yeast’s phenotype and are inherited in a non-Mendelian fashion (for review, see [ 2 ]). Most yeast prion aggregates have amyloid nature, i.e., their prion conformers form long fibrillar structures with a typical regular structure (for review, see [ 3 , 4 , 5 ]).…”

Section: Introductionmentioning

confidence: 99%

Processing of Fluorescent Proteins May Prevent Detection of Prion Particles in [PSI+] Cells

Matveenko

Ryzhkova

Zaytseva

et al. 2022

Biology

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Yeast is a convenient model for studying protein aggregation as it is known to propagate amyloid prions. [PSI+] is the prion form of the release factor eRF3 (Sup35). Aggregated Sup35 causes defects in termination of translation, which results in nonsense suppression in strains carrying premature stop codons. N-terminal and middle (M) domains of Sup35 are necessary and sufficient for maintaining [PSI+] in cells while preserving the prion strain’s properties. For this reason, Sup35NM fused to fluorescent proteins is often used for [PSI+] detection and investigation. However, we found that in such chimeric constructs, not all fluorescent proteins allow the reliable detection of Sup35 aggregates. Particularly, transient overproduction of Sup35NM-mCherry resulted in a diffuse fluorescent pattern in the [PSI+] cells, while no loss of prions and no effect on the Sup35NM prion properties could be observed. This effect was reproduced in various unrelated strain backgrounds and prion variants. In contrast, Sup35NM fused to another red fluorescent protein, TagRFP-T, allowed the detection of [PSI+] aggregates. Analysis of protein lysates showed that Sup35NM-mCherry is actively degraded in the cell. This degradation was not caused by vacuolar proteases and the ubiquitin-proteasomal system implicated in the Sup35 processing. Even though the intensity of this proteolysis was higher than that of Sup35NM-GFP, it was roughly the same as in the case of Sup35NM-TagRFP-T. Thus, it is possible that, in contrast to TagRFP-T, degradation products of Sup35NM-mCherry still preserve their fluorescent properties while losing the ability to decorate pre-existing Sup35 aggregates. This results in diffuse fluorescence despite the presence of the prion aggregates in the cell. Thus, tagging with fluorescent proteins should be used with caution, as such proteolysis may increase the rate of false-negative results when detecting prion-bearing cells.

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Beyond Amyloid Fibers: Accumulation, Biological Relevance, and Regulation of Higher-Order Prion Architectures

Cited by 5 publications

References 137 publications

The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation

The yeast molecular chaperone, Hsp104, influences transthyretin aggregate formation

SARS-CoV-2 Invasion and Pathological Links to Prion Disease

Processing of Fluorescent Proteins May Prevent Detection of Prion Particles in [PSI+] Cells

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