Polythiophenes Inhibit Prion Propagation by Stabilizing Prion Protein (PrP) Aggregates

Margalith, Ilan; C, Suter; Ballmer, Boris; Schwarz, Petra; Tiberi, Cinzia; Sonati, Tiziana; Falsig, Jeppe; Nyström, Sofie; Hammarström, Per; Åslund, Andreas; Nilsson, K. Peter R.; Yam, Alice; Whitters, Eric A.; Hornemann, Simone; Aguzzi, Adriano

doi:10.1074/jbc.m112.355958

Cited by 63 publications

(79 citation statements)

References 84 publications

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“…Similarly to Ab, small PrP oligomeric structures are the most infectious prion species (Silveira et al 2005). In addition, the stabilization of PrP fibrils was found to reduce infectivity (Margalith et al 2012). Together, these observations suggest that the assemblage of PrP oligomers to create large prion rods reduces toxicity.…”

Section: The Deposition Of Aggregates Is a Hallmark Of Neurodegeneratmentioning

confidence: 92%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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Section: The Deposition Of Aggregates Is a Hallmark Of Neurodegeneratmentioning

confidence: 92%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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“…A fibril that never breaks would be relatively harmless because it would be unable to maintain the disease-generating process. Substances that reduce aggregate frangibility are therapeutic [6,7]. Note, however, that this model of cyclical propagon amplification does not explain the toxicity associated with the deposition of protein Trends Protein misfolding and aggregation is the root cause of many neurodegenerative disorders.…”

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confidence: 99%

Cell Biology of Prions and Prionoids: A Status Report

Aguzzi

Lakkaraju

2016

Trends in Cell Biology

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132

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“…Moreover, p-FTAA was previously demonstrated to stabilize prion proteins [226]. Aβ aggregated with p-FTAA exhibited both an increased resistance towards degradation with proteinase K and a high resistance to the harsh denaturant Gdn-HCl, which suggest a more compact formation of the Aβ fibrils.…”

Section: Paper Iv: Lysozyme Attenuates the Cellular Uptake Of Amyloid-βmentioning

confidence: 93%

“…It was previously shown that p-FTAA was able to decrease the infectiousness of prion aggregates [226,227], which prompted us to investigate the seeding effect of Aβ to the orcein-related compound O4 and curcumin that previously were shown to enhance the aggregation of Aβ and thereby reduce toxicity [155,156]. Moreover, p-FTAA was previously demonstrated to stabilize prion proteins [226].…”

Section: Paper Iv: Lysozyme Attenuates the Cellular Uptake Of Amyloid-βmentioning

confidence: 99%

The influence of lysozyme and oligothiophenes on amyloid-β toxicity in models of Alzheimer’s disease

Sandin¹

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Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia worldwide. Apart from dominantly inherited mutations, age is the major risk factor and as life expectancy increases the prevalence for AD escalates dramatically. AD causes substantial problems for the affected persons and their families, and the society suffers economically. To date the available treatments only temporarily relieve the symptoms, wherefore the development of a cure is of utmost importance. The etiology of AD is still inconclusive but many believe that small aggregates (oligomers) of the protein amyloid-β (Aβ) are central for the onset of AD. The aims of this thesis were to investigate how different molecules affect the aggregation and toxicity of Aβ. In paper I and II, two oligothiophenes were studied; p-FTAA and h-FTAA and in paper III and IV the inflammatory protein lysozyme was explored. Differentiated neuroblastoma cells and Drosophila melanogaster were used as models of AD to address the issue. The results show that p-FTAA rescues neuroblastoma cells from Aβ toxicity when Aβ is coaggregated with lysozyme. Various biophysical studies show that the co-aggregation increases the formation of fibrillar Aβ structures rich in β-sheets. Noteworthy, these Aβ fibrils were more resistant to both degradation and denaturation, and less prone to propagate seeding from Aβ monomers. Furthermore, h-FTAA, but not p-FTAA, was able to protect neuroblastoma cell toxicity when exposed to Aβ with the Arctic mutation (AβArc), which probably reflects the weaker binding of AβArc to p-FTAA, compared to h-FTAA. Lysozyme levels were increased in CSF from patients that were both biochemically and clinically diagnosed with AD. In mice models of AD it was revealed that the mRNA increase in lysozyme correlates to increased Aβ pathology, but not to tau pathology, indicating that Aβ could drive the expression of lysozyme. To evaluate the effect for increased expression of lysozyme, co-expression of lysozyme was achieved in flies that expressed Aβ in the retina of the eyes, or in flies that expressed AβArc in the central nervous system. In all AD fly models, co-expression of lysozyme protected the cells from the Aβ induced toxicity. Of note, flies that expressed the toxic AβArc in the CNS of the flies showed an improvement in both lifespan and activity. Finally, we demonstrate that Aβ aggregating in the presence of lysozyme inhibits the cellular uptake of Aβ and also the cytotoxic effect of Aβ. The work included in this thesis demonstrates that the oligothiophenes p-FTAA and h-FTAA, and also lysozyme have the potential to be used as treatment strategies for sporadic AD, but remarkable, also in familial AD with the highly toxic Arctic mutation. The protective mechanism of p-FTAA seems to be attributed to the ability to generate stable Aβ fibrils with reduced seeding capacity, and that lysozyme inhibits the neuronal uptake of Aβ, which could prevent both the intracellular toxicity and cell-to-cell transmission of Aβ.

Funded by: Stiftel...

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Polythiophenes Inhibit Prion Propagation by Stabilizing Prion Protein (PrP) Aggregates

Cited by 63 publications

References 84 publications

Protein Quality Control in Health and Disease

Protein Quality Control in Health and Disease

Cell Biology of Prions and Prionoids: A Status Report

The influence of lysozyme and oligothiophenes on amyloid-β toxicity in models of Alzheimer’s disease

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