An inherited prion disease with a PrP P105L mutation

Yamada, Masahito; Itoh, Yoshinori; Inaba, Akira; Wada, Yoshiaki; Takashima, Minoru; Satoh, Sakae; Kamata, Tomoyuki; Okeda, Riki; Kayano, Teruo; Suematsu, Naomi; Kitamoto, Tetsuyuki; Otomo, E; Matsushita, M.; Mizusawa, Hidehiro

doi:10.1212/wnl.53.1.181

Cited by 47 publications

(43 citation statements)

References 22 publications

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“…Implication for the Role of Proline Mutants on Familial Amyloidosis-Several mutations with Pro substituted by other amino acids or mutations in which Pro is newly introduced are found in several types of familial amyloidosis (11,(43)(44)(45)(46). The substitution of a certain amino acid (Xaa) with Pro is assumed to cause serious perturbation of the structure of native and/or intermediate states and increases the amyloidogenicity of these mutants (11).…”

Section: Discussionmentioning

confidence: 99%

Amyloid Fibril Formation in the Context of Full-length Protein

Chiba

Hagihara

Higurashi

et al. 2003

Journal of Biological Chemistry

116

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␤ 2 -Microglobulin (␤2-m), a typical immunoglobulin domain made of seven ␤-strands, is a major component of amyloid fibrils formed in dialysis-related amyloidosis. To understand the mechanism of amyloid fibril formation in the context of full-length protein, we prepared various mutants in which proline (Pro) was introduced to each of the seven ␤-strands of ␤2-m. The mutations affected the amyloidogenic potential of ␤2-m to various degrees. In particular, the L23P, H51P, and V82P mutations significantly retarded fibril extension at pH 2.5. Among these, only L23P is included in the known "minimal" peptide sequence, which can form amyloid fibrils when isolated as a short peptide. This indicates that the residues in regions other than the minimal sequence, such as H51P and V82P, determine the amyloidogenic potential in the full-length protein. To further clarify the mutational effects, we measured their stability against guanidine hydrochloride of the native state at pH 8.0 and the amyloid fibrils at pH 2.5. The amyloidogenicity of mutants showed a significant correlation with the stability of the amyloid fibrils, and little correlation was observed with that of the native state. It has been proposed that the stability of the native state and the unfolding rate to the amyloidogenic precursor as well as the conformational preference of the denatured state determine the amyloidogenicity of the proteins. The present results reveal that, in addition, stability of the amyloid fibrils is a key factor determining the amyloidogenic potential of the proteins.More than 20 diseases are related to the deposition of insoluble amyloid fibrils (1-3). In some cases, such as Alzheimer's disease, fibril components are the truncated relatively short fragments of amyloid precursor proteins. In other types of amyloidosis, such as familial amyloid polyneuropathy and dialysis-related amyloidosis, amyloid fibrils are made of the entire part of the originally globular proteins. For these proteins, it has been shown that short peptides, called minimal (or essential) sequences, can also form amyloid fibrils (4 -7). These findings raise the question of whether regions other than the minimal sequence affect the amyloid fibril formation.For many amyloidogenic globular proteins, destabilization of the native globular state by mutation or by introduction of unstable conditions is highly correlated with the formation of amyloid fibrils, suggesting that the denaturation or unfolding of the native state is the critical event in triggering amyloid formation (8 -12). A study with a series of transthyretin mutants revealed that the unfolding rate rather than the thermodynamic stability is an important factor determining amyloidogenicity (13). Alternatively, because the non-native state is an intermediate or precursor of amyloid fibril formation, residues other than the minimal region can control amyloid fibril formation by affecting the conformational properties of the non-native state. Consistent with this, recent studies with various mutants of acylph...

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Section: Discussionmentioning

confidence: 99%

Amyloid Fibril Formation in the Context of Full-length Protein

Chiba

Hagihara

Higurashi

et al. 2003

Journal of Biological Chemistry

116

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“…A leucine substitution (P105L) was initially reported in several Japanese families [22][23][24] and a threonine substitution (P105T) was subsequently detected in a Canadian family. 25 The polymorphic codon 129, which is known to affect prion disease phenotype, is Val on the mutated allele in both P105S and P105L, but Met on the P105T allele.…”

Section: Figure 3 Prp Amyloid In Prnp-p105smentioning

confidence: 99%

“…The clinicopathologic picture most associated with P105L has been the development of spastic paraparesis in the absence of prominent ataxia, the diffuse deposition of GSS-type plaques, and the absence of spongiform degeneration. 24 Although the histologic profile of P105T has not been described, ataxia and dementia were the principal clinical features reported. 25 These descriptions differ from our case that presented with features initially suggesting FTD with parkinsonism, including aphasia, prominent behavioral changes, and severe parkinsonism, and a histologic profile that includes an unusual distribution of GSS type plaques and intense focus of spongiform degeneration in the putamen.…”

Section: Figure 3 Prp Amyloid In Prnp-p105smentioning

confidence: 99%

“…However, the unusual rPrP Sc pattern, a measure of PrP Sc conformation, clearly distinguishes this disease not only from P105L-related disease, but all other cases of GSS and other GSS variants. 24 As such, it could also be argued that this represents a distinct prion subtype. Strain testing by transmission to susceptible transgenic mice is under way to assist in this determination.…”

Section: Figure 3 Prp Amyloid In Prnp-p105smentioning

confidence: 99%

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A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP ^Sc conformation

Tunnell¹,

Wollman²,

Mallik³

et al. 2008

Neurology

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Objective: To define the clinicopathologic, genetic, and pathogenic prion protein (PrP Sc ) characteristics associated with a novel mutation of the prion protein gene (PRNP). Methods:The coding segment of PRNP from the proband and family members was sequenced and the brain of the proband was histologically studied. The Western blot profile of the proteinase K (PK) resistant fraction of PrP Sc , an approximation of its conformation, or "PrP Sc -type," was determined.Results: We detected a novel mutation at codon 105 of PRNP that results in a serine (S) substitution of proline (P) (P105S), in a young woman who developed progressive aphasia, behavioral changes, dementia, and parkinsonism, lasting 10 years to her death. Histopathologic findings included an intense focus of multicentric PrP-plaques within the hippocampus, punctate plaques scattered throughout the cerebellum, and intense spongiform degeneration focally within the putamen, suggesting a variant of Gerstmann-Sträussler-Scheinker syndrome (GSS). However, PrP Sc -typing revealed two PK-resistant PrP Sc fragments (ϳ21 and 26 kDa), a pattern not previously detected in GSS.Conclusions: This mutation is the third sequence variation at codon 105 of PRNP. The unusual phenotype and PrP Sc -type distinguishes this genetic prion disease from typical GerstmannSträussler-Scheinker syndrome and other codon 105 substitutions, suggesting that, in addition to the loss of proline at this position, the PrP Sc conformation and phenotype is dependent on the specific amino acid substitution. Neurology ® 2008;71:1431-1438 GLOSSARY fCJD ϭ familial Creutzfeldt-Jakob disease; FFI ϭ familial fatal insomnia; FTD ϭ frontotemporal dementia; GSS ϭ GerstmannSträussler-Scheinker syndrome; PK ϭ proteinase K.The prion diseases are a family of transmissible neurodegenerative disorders that result from the accumulation of a misfolded isoform (PrP Sc ) of the normal prion protein (PrP C ). 1 Over 30 missense and insertional mutations of the PrP gene (PRNP) lead to the varied expression of three major heritable forms of disease, including familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and familial fatal insomnia (FFI). 2 These prion subtypes are distinguished from each other somewhat by their clinical presentation, but primarily by their associated histopathology. Extensive spongiform degeneration denotes CJD, focal thalamic gliosis and neuronal loss defines FFI, and PrP amyloid plaque deposits characterize GSS. Evidence suggests these phenotypes are enciphered in the conformation of the associated misfolded PrP (PrP Sc ), 3-5 which can be approximated by the Western blot pattern of proteinase K (PK) resistant PrP Sc (rPrP Sc ) within the affected brain. In fCJD and FFI, rPrP Sc displays three fractions with migration rates (M r ) ranging from ϳ19 or 21-33 kiloDaltons (kDa), representing un-, mono-, and di-glycosylated rPrP Sc , whereas a single unglycosylated fragment of ϳ6 -11 kDa is typically detected in GSS. 6

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“…This mutation was found in 5 GSS families, all from Japan [99][100][101][102][103][104][105][106]. The disease manifests as spastic paraparesis with brisk tendom reflexes and the presence of Babinski sign; in terminal stages, patients become teraplegic, demented, with tremor and limb rigidity.…”

Section: The Codon 105 Leu 129 Val Mutationmentioning

confidence: 99%

Molecular Genetics of Gerstmann-Straussler-Scheinker Disease and Creutzfeld-Jakob Disease

Surewicz¹

2013

Hereditary Genetics

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Prion diseases are a group of transmissible neurodegenerative disorders associated with the misfolded form of the prion protein, PrP Sc . The latter isoform is derived by conformational conversion of the normal prion protein, PrP c . The gene encoding the prion protein is highly conserved among species. There are several distinct types of prion diseases in humans: kuru, Creutzfeldt -Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS) and Fatal Familial Insomnia (FFI) and its sporadic analogue, fatal sporadic insomnia. While human prion diseases are mostly sporadic, some 15% of CJD and all cases of GSS are hereditary disorders caused by mutations in the PRNP gene. There are two major types of mutations in PRNP: point mutations leading to amino acid substitutions and mutations leading to expansions of the octapeptide repeat region within the N-terminal part of the prion protein. This review describes different types of familial prion diseases linked to specific polymorphisms and mutation in PRNP.

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An inherited prion disease with a PrP P105L mutation

Abstract: Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic differences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.

Cited by 47 publications

References 22 publications

Amyloid Fibril Formation in the Context of Full-length Protein

Amyloid Fibril Formation in the Context of Full-length Protein

A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP ^Sc conformation

Molecular Genetics of Gerstmann-Straussler-Scheinker Disease and Creutzfeld-Jakob Disease

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An inherited prion disease with a PrP P105L mutation

Abstract: Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic differences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.

Cited by 47 publications

References 22 publications

Amyloid Fibril Formation in the Context of Full-length Protein

Amyloid Fibril Formation in the Context of Full-length Protein

A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP Sc conformation

Molecular Genetics of Gerstmann-Straussler-Scheinker Disease and Creutzfeld-Jakob Disease

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A novel PRNP -P105S mutation associated with atypical prion disease and a rare PrP ^Sc conformation