Trans‐seeding of Alzheimer‐related tau protein by a yeast prion

Flach, Martin; Leu, Cedric; Martinisi, Alfonso; Skachokova, Zhiva; Frank, Stephan; Tolnay, Markus; Stahlberg, Henning; Winkler, David T.

doi:10.1002/alz.12581

Cited by 6 publications

(5 citation statements)

References 78 publications

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“…However, one should note that the recent evidence increasingly points to the ability of some prion and other amyloid proteins to cross-seed non-homologous substrates. Cross-seeding interactions have been described between protein as distant as yeast Sup35 and human tau ( Flach et al, 2022 ) or bacterial curli and human synuclein ( Sampson et al, 2020 ). Even though these cross-seeding interactions are less efficient than homologous seeding, the possibility of the existence of highly promiscuous prions with broad cross-seeding capabilities cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Heat inactivation of stable proteinaceous particles for future sample return mission architecture

et al. 2022

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The National Aeronautics and Space Administration (NASA) and the European Space Agency (ESA) are studying how to improve the safety of future planetary science sample return missions that would bring back materials to Earth. Backward planetary protection requirements have been identified as a critical technology development focus in order to reduce the possibility of harm to Earth’s biosphere from such returned materials. In order to meet these challenges, NASA has identified the need for an appropriate suite of biological indicators (BIs) that would be used to develop, test, and ultimately validate sample return mission sterilization systems. Traditionally, BIs are defined as test systems composed of viable microorganisms that are inactivated when necessary conditions are met during sterilization procedures, providing a level of confidence in the process. BIs used traditionally at NASA have been driven by past mission requirements, mainly focused on spore-formers. However, spore-based BIs are insufficient as the only analog for a nominal case in sample return missions. NASA has directed sample return missions from habitable worlds to manage “potential extraterrestrial life and bioactive molecules” which requires investigation of a range of potential BIs. Thus, it is important to develop a mitigation strategy that addresses various known forms of biology, from complex organisms to biomolecular assemblies (including self-perpetuating non-nucleic acid containing structures). The current effort seeks to establish a BI that would address a stable biomolecule capable of replication. Additional engineering areas that may benefit from this information include applications of brazing, sealing, and impact heating, and atmospheric entry heating. Yeast aggregating proteins exhibit aggregation behavior similar to mammalian prion protein and have been successfully employed by researchers to understand fundamental prion properties such as aggregation and self-propagation. Despite also being termed “prions,” yeast proteins are not hazardous to humans and can be used as a cost effective and safer alternative to mammalian prions. We have shown that inactivation by dry heat is feasible for the prion formed by the yeast Sup35NM protein, although at higher temperature than for bacterial spores.

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Section: Discussionmentioning

confidence: 99%

Heat inactivation of stable proteinaceous particles for future sample return mission architecture

et al. 2022

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“…Most age-related neurodegenerative diseases, including AD, occur with the misfolding and aggregation of specific proteins within the nervous system ( Condello et al, 2020 ; Flach et al, 2022 ). Such diseases are called protein misfolding diseases or proteinopathies and share similar biophysical and biochemical characteristics to prion diseases.…”

Section: Alzheimer’s Disease-related Tau Pathological Changesmentioning

confidence: 99%

“…Such diseases are called protein misfolding diseases or proteinopathies and share similar biophysical and biochemical characteristics to prion diseases. In AD, Aβ and tau proteins are called “prion-like molecules,” indicating that they have prion-like biological properties ( Flach et al, 2022 ). Aβ and tau protein are induced to misfold by a templated structural change.…”

Section: Alzheimer’s Disease-related Tau Pathological Changesmentioning

confidence: 99%

“…The misfolded molecules can not only further influence the normal molecules to make their structural changes, but also easily aggregate to form a subset aggregator ( Hooper and Turner, 2008 ; Di Guardo, 2018 ; Li et al, 2021 ). Such abnormal molecular aggregates can cause lesions in the local parts of the brain tissue, and through the cellular transmission of the subaggregates, the tissue damage is also dispersed far ( Flach et al, 2022 ; Zattoni et al, 2022 ).…”

Section: Alzheimer’s Disease-related Tau Pathological Changesmentioning

confidence: 99%

“…It does not contain nucleic acids, but can replicate itself and is infectious. The pathogen can cross the blood-brain barrier, slowly destroying the structure of brain tissue and eventually killing the patient ( Di Guardo, 2018 ; Flach et al, 2022 ). Alzheimer’s disease is a “diprion” disease in which Aβ and tau tangles in a patient’s brain can infect healthy brain tissue just like prion proteins, only this time at a much slower rate ( Kent et al, 2020 ).…”

Section: Alzheimer’s Disease-related Tau Pathological Changesmentioning

confidence: 99%

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Biomarkers associated with the pathogenesis of Alzheimer’s disease

Wang,

Sun,

et al. 2023

Front. Cell. Neurosci.

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Alzheimer’s disease (AD) is a progressive degenerative neurological illness with insidious onset. Due to the complexity of the pathogenesis of AD and different pathological changes, the clinical phenotypes of dementia are diverse, and these pathological changes also interact with each other. Therefore, it is of great significance to search for biomarkers that can diagnose these pathological changes to improve the ability to monitor the course of disease and treat the disease. The pathological mechanism hypothesis with high recognition of AD mainly includes the accumulation of β-amyloid (Aβ) around neurons and hyperphosphorylation of tau protein, which results in the development of neuronal fiber tangles (NFTs) and mitochondrial dysfunction. AD is an irreversible disease; currently, there is no clinical cure or delay in the disease process of drugs, and there is a lack of effective early clinical diagnosis methods. AD patients, often in the dementia stages and moderate cognitive impairment, will seek medical treatment. Biomarkers can help diagnose the presence or absence of specific diseases and their pathological processes, so early screening and diagnosis are crucial for the prevention and therapy of AD in clinical practice. β-amyloid deposition (A), tau pathology (T), and neurodegeneration/neuronal damage (N), also known as the AT (N) biomarkers system, are widely validated core humoral markers for the diagnosis of AD. In this paper, the pathogenesis of AD related to AT (N) and the current research status of cerebrospinal fluid (CSF) and blood related biomarkers were reviewed. At the same time, the limitations of humoral markers in the diagnosis of AD were also discussed, and the future development of humoral markers for AD was prospected. In addition, the contents related to mitochondrial dysfunction, prion virology and intestinal microbiome related to AD are also described, so as to understand the pathogenesis of AD in many aspects and dimensions, so as to evaluate the pathological changes related to AD more comprehensively and accurately.

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Trans‐seeding of Alzheimer‐related tau protein by a yeast prion

Flach

Leu

Martinisi

et al. 2022

Alzheimer's & Dementia

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Abnormal tau protein aggregates constitute a hallmark of Alzheimer's disease. The mechanisms underlying the initiation of tau aggregation in sporadic neurodegeneration remain unclear. Here we investigate whether a non-human prion can seed tau aggregation. Due to their structural similarity with tau aggregates, we chose Sup35NM yeast prion domain fibrils for explorative tau seedings. Upon in vitro incubation with tau monomers, Sup35NM fibrils promoted the formation of morphologically distinct tau fibril strains. In vivo, intrahippocampal inoculation of Sup35NM fibrils accentuated tau pathology in P301S tau transgenic mice. Thus, our results provide first in vivo evidence for heterotypic cross-species seeding of a neurodegenerative human prion-like protein by a yeast prion. This opens up the conceptual perspective that nonmammalian prions present in the human microbiome could be involved in the initiation of protein misfolding in neurodegenerative disorders, a mechanism for which we propose the term "trans-seeding."

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Trans‐seeding of Alzheimer‐related tau protein by a yeast prion

Cited by 6 publications

References 78 publications

Heat inactivation of stable proteinaceous particles for future sample return mission architecture

Heat inactivation of stable proteinaceous particles for future sample return mission architecture

Biomarkers associated with the pathogenesis of Alzheimer’s disease

Trans‐seeding of Alzheimer‐related tau protein by a yeast prion

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