Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation

Kraus, Allison; Anson, Kelsie J.; Raymond, Lynne D.; Martens, Craig; Groveman, Bradley R.; Dorward, David W.; Caughey, Byron

doi:10.1074/jbc.m115.665844

Cited by 23 publications

(31 citation statements)

References 47 publications

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“…In particular, seven point mutations, of PRNP codon 102, 105, 117, 145, 198, 202 and 217, have been detected in GSS patients. The most frequent is point mutation P102L (Takazawa et al, 2010;Collins et al, 2001;Ortega-Cubero et al, 2013;Kraus et al, 2015). Mutations of the PRNP gene induce a change in the conformation of the normal PrP c protein to the pathological form PrP sc (Chen and Dong, 2016;Huang et al, 2015;Araújo, 2013;Kraus et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…The most frequent is point mutation P102L (Takazawa et al, 2010;Collins et al, 2001;Ortega-Cubero et al, 2013;Kraus et al, 2015). Mutations of the PRNP gene induce a change in the conformation of the normal PrP c protein to the pathological form PrP sc (Chen and Dong, 2016;Huang et al, 2015;Araújo, 2013;Kraus et al, 2015). The resulting accumulation of PrP sc in the lysosomes causes them to swell and eventually burst, thereby releasing the damaging proteolytic enzymes and PrP sc into the cell (Araújo, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Quantitative, functional MRI and neurophysiological markers in a case of Gerstmann-Str�ussler-Scheinker syndrome

Marıno

Morabito

Salvo

et al. 2017

Functional Neurology

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SummaryGerstmann-Sträussler-Scheinker syndrome (GSS) is an inherited autosomal dominant prion disease, caused by a codon 102 proline to leucine substitution (P102L) in the prion protein gene (PRNP). We describe the case of a 40-year-old male, affected by a slowly progressive gait disturbance, leg weakness and cognitive impairment. Genomic DNA revealed a point mutation of PRNP at codon 102, resulting in P102L, and the diagnosis of GSS was confirmed. Somatosensory evoked potentials showed alterations of principal parameters, particularly in the right upper and lower limbs. Laser-evoked potentials were indicative of nociceptive system impairment, especially in the right upper and lower limbs. Conventional magnetic resonance imaging (MRI) revealed marked atrophy of the vermis and cerebellar hemispheres and mild atrophy of the middle cerebellar peduncles and brainstem, as confirmed by a brain volume automatic analysis. Resting-state functional MRI showed increased functional connectivity in the bilateral visual cortex, and decreased functional connectivity in the bilateral frontal pole and supramarginal and precentral gyrus. Albeit limited to a single case, this is the first study to assess structural and functional connectivity in GSS using a multimodal approach.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Quantitative, functional MRI and neurophysiological markers in a case of Gerstmann-Str�ussler-Scheinker syndrome

Marıno

Morabito

Salvo

et al. 2017

Functional Neurology

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“…De novo prion formation in vitro typically requires the addition of cofactors. Here, we tested whether proline and lysine residues previously shown to impede PrP amyloid formation (27,28) and interact with a polyanionic cofactor needed for de novo prion generation (29) could influence the ability of PrP amyloid seeds to propagate in vivo. We generated PrP amyloids in the absence of cofactors from recombinant PrP containing the P102L mutation alone or in combination with substitutions of the 4 nearby lysines (K) with asparagines (N) (K 4 NP102L) (Fig.…”

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confidence: 99%

“…1A). These substitutions neutralized the positive charge of the lysine side chains, thus mimicking the charge-neutralizing effects of the binding of a polyanionic cofactor (27)(28)(29). We also tested the simultaneous change of all 4 lysines to asparagines and of both prolines to alanines (K 4 NP 2 A) ( Fig.…”

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PrP P102L and Nearby Lysine Mutations Promote Spontaneous In Vitro Formation of Transmissible Prions

Kraus

Raymond

Race

et al. 2017

J Virol

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Accumulation of fibrillar protein aggregates is a hallmark of many diseases. While numerous proteins form fibrils by prion-like seeded polymerization , only some are transmissible and pathogenic To probe the structural features that confer transmissibility to prion protein (PrP) fibrils, we have analyzed synthetic PrP amyloids with or without the human prion disease-associated P102L mutation. The formation of infectious prions from PrP molecules has required cofactors and/or unphysiological denaturing conditions. Here, we demonstrate that, under physiologically compatible conditions without cofactors, the P102L mutation in recombinant hamster PrP promoted prion formation when seeded by minute amounts of scrapie prions Surprisingly, combination of the P102L mutation with charge-neutralizing substitutions of four nearby lysines promoted spontaneous prion formation. When inoculated into hamsters, both of these types of synthetic prions initiated substantial accumulation of prion seeding activity and protease-resistant PrP without transmissible spongiform encephalopathy (TSE) clinical signs or notable glial activation. Our evidence suggests that PrP's centrally located proline and lysine residues act as conformational switches in the formation of transmissible PrP amyloids. Many diseases involve the damaging accumulation of specific misfolded proteins in thread-like aggregates. These threads (fibrils) are capable of growing on the ends by seeding the refolding and incorporation of the normal form of the given protein. In many cases such aggregates can be infectious and propagate like prions when transmitted from one individual host to another. Some transmitted aggregates can cause fatal disease, as with human iatrogenic prion diseases, while other aggregates appear to be relatively innocuous. The factors that distinguish infectious and pathogenic protein aggregates from more innocuous ones are poorly understood. Here we have compared the combined effects of prion seeding and mutations of prion protein (PrP) on the structure and transmission properties of synthetic PrP aggregates. Our results highlight the influence of specific sequence features in the normally unstructured region of PrP that influence the infectious and neuropathogenic properties of PrP-derived aggregates.

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Seed amplification and RT-QuIC assays to investigate protein seed structures and strains

Standke

Kraus

2022

Cell Tissue Res

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Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation

Cited by 23 publications

References 47 publications

Quantitative, functional MRI and neurophysiological markers in a case of Gerstmann-Str�ussler-Scheinker syndrome

Quantitative, functional MRI and neurophysiological markers in a case of Gerstmann-Str�ussler-Scheinker syndrome

PrP P102L and Nearby Lysine Mutations Promote Spontaneous In Vitro Formation of Transmissible Prions

Seed amplification and RT-QuIC assays to investigate protein seed structures and strains

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