Detection of tau in Gerstmann-Sträussler-Scheinker disease (PRNP F198S) by [18F]Flortaucipir PET

Risacher, Shannon L.; Farlow, Martin R.; Bateman, Daniel R.; Epperson, Francine; Tallman, Eileen F.; Richardson, Rose; Murrell, Jill R.; Unverzagt, Frederick W.; Apostolova, Liana G.; Bonnin, José M.; Ghetti, Bernardino; Saykin, Andrew J.

doi:10.1186/s40478-018-0608-z

Cited by 13 publications

(13 citation statements)

References 36 publications

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“…Genomic DNA was extracted from frozen brain tissue. Polymerase chain reaction (PCR) was performed for the amplification of the PRNP and AβPP genes as described [ 44 , 51 ]. PCR products were sequenced on a CEQ 2000XL DNA analysis system (Beckman Coulter, Fullerton, CA).…”

Section: Methodsmentioning

confidence: 99%

Structure of Tau filaments in Prion protein amyloidoses

et al. 2021

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In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

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Section: Methodsmentioning

confidence: 99%

Structure of Tau filaments in Prion protein amyloidoses

et al. 2021

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“…Pronounced and early abnormalities in eye movements, such as a progressive supranuclear palsy, are a unique feature related to subcortical tau deposition in the GSS Indiana kindred [4, 5]. GSS is a neurodegenerative prion disease with diverse clinical presentations.…”

Section: Resultsmentioning

confidence: 99%

“…In the Indiana Kindred, a point mutation in in codon 198 of the prion protein (PRNP) gene results in amyloid deposits predominantly located in the inner cortical layers [3]. In addition to amyloid deposition, this kindred uniquely features intraneuronal deposits of hyperphosphorylated tau and neurofibrillary tangles in the cortex and subcortical nuclei [1, 4].…”

Section: Discussionmentioning

confidence: 99%

A case of Gerstmann-Straussler-Scheinker (GSS) disease with supranuclear gaze palsy

2019

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BackgroundGerstmann-Straussler-Scheinker disease (GSS), an autosomal dominant prion disorder, usually presents as a slowly progressive cerebellar ataxia followed by later cognitive decline. We present a member of the GSS Indiana Kindred with supranuclear palsy, a less common feature in GSS.Case presentationA 42-year-old man presented with 12 months of progressive gait and balance difficulty. Exam was notable for ataxia and cerebellar eye movement abnormalities. Genetic testing revealed a F198S variant in the prion protein (PRNP) gene, the pathological variant of GSS associated with his family, the Indiana kindred. Eighteen months after initial presentation supranuclear palsy developed.ConclusionsGSS is a neurodegenerative prion disease with diverse clinical presentations, and exhibits greater variability in disease phenotype compared to other inherited spongiform encephalopathies. GSS should be on the differential for patients with ataxia and supranuclear palsy, and it is important to assess both horizontal and vertical saccades and optokinetic nystagmus in patients with ataxia.

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“…Brain tissue samples were fixed for 3-4 weeks in buffered 10% formalin. Then, using the BrainNet Europe standardized protocol [33], selected tissue blocks were embedded in paraffin using an automatic tissue processor. Sections 5 µm thick were prepared and stained with hematoxylin-eosin, Klüver-Barrera, and silver impregnation methods.…”

Section: Tissue Samplesmentioning

confidence: 99%

Extracellular Prion Protein Aggregates in Nine Gerstmann–Sträussler–Scheinker Syndrome Subjects with Mutation P102L: A Micromorphological Study and Comparison with Literature Data

Jankovska

Matěj

Olejár

2021

IJMS

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Gerstmann–Sträussler–Scheinker syndrome (GSS) is a hereditary neurodegenerative disease characterized by extracellular aggregations of pathological prion protein (PrP) forming characteristic plaques. Our study aimed to evaluate the micromorphology and protein composition of these plaques in relation to age, disease duration, and co-expression of other pathogenic proteins related to other neurodegenerations. Hippocampal regions of nine clinically, neuropathologically, and genetically confirmed GSS subjects were investigated using immunohistochemistry and multichannel confocal fluorescent microscopy. Most pathognomic prion protein plaques were small (2–10 µm), condensed, globous, and did not contain any of the other investigated proteinaceous components, particularly dystrophic neurites. Equally rare (in two cases out of nine) were plaques over 50 µm having predominantly fibrillar structure and exhibit the presence of dystrophic neuritic structures; in one case, the plaques also included bulbous dystrophic neurites. Co-expression with hyperphosphorylated protein tau protein or amyloid beta-peptide (Aβ) in GSS PrP plaques is generally a rare observation, even in cases with comorbid neuropathology. The dominant picture of the GSS brain is small, condensed plaques, often multicentric, while presence of dystrophic neuritic changes accumulating hyperphosphorylated protein tau or Aβ in the PrP plaques are rare and, thus, their presence probably constitutes a trivial observation without any relationship to GSS development and progression.

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Detection of tau in Gerstmann-Sträussler-Scheinker disease (PRNP F198S) by [18F]Flortaucipir PET

Cited by 13 publications

References 36 publications

Structure of Tau filaments in Prion protein amyloidoses

Structure of Tau filaments in Prion protein amyloidoses

A case of Gerstmann-Straussler-Scheinker (GSS) disease with supranuclear gaze palsy

Extracellular Prion Protein Aggregates in Nine Gerstmann–Sträussler–Scheinker Syndrome Subjects with Mutation P102L: A Micromorphological Study and Comparison with Literature Data

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