Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene

doi:10.1016/0169-328X(95)00175-R

Molecular Brain Research

Volume 34, Issue 1, 1 December 1995, Pages 173-176

https://doi.org/10.1016/0169-328X(95)00175-R Get rights and content

Abstract

Some cases of spongiform encephalopathies are linked to mutations within the prion protein gene (PRNP). Repetitive octapeptide insertions of variable length in the PRNP gene are also associated with spongiform encephalopathies, mostly familial Creutzfeldt-Jakob disease (CJD). In this study we report on a novel insertion mutation comprising nine extra octapeptide repeats between codons 51 and 91 of the PRNP gene. The affected patient showed a slowly progressive dementia of at least 6 years duration and ataxia.

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Cited by (94)

Dominantly inherited prion protein cerebral amyloidoses – a modern view of Gerstmann–Sträussler–Scheinker
2018, Handbook of Clinical Neurology
Among genetically determined neurodegenerative diseases, the dominantly inherited prion protein cerebral amyloidoses are characterized by deposition of amyloid in cerebral parenchyma or blood vessels. Among them, Gerstmann–Sträussler–Scheinker disease has been the first to be described. Their clinical, neuropathologic, and molecular phenotypes are distinct from those observed in Creutzfeldt–Jakob disease (CJD) and related spongiform encephalopathies. It is not understood why specific mutations in the prion protein gene (PRNP) cause cerebral amyloidosis and others cause CJD. A significant neurobiologic event in these amyloidoses is the frequent coexistence of prion amyloid with tau neurofibrillary pathology, a phenomenon suggesting that similar pathogenetic mechanisms may be shared among different diseases in the sequence of events occurring in the cascade from amyloid formation to tau aggregation. This chapter describes the clinical, neuropathologic, and biochemical phenotypes associated with each of the PRNP mutations causing an inherited cerebral amyloidosis and emphasizes the variability of phenotypes.
Prion disease
2018, Handbook of Clinical Neurology
Genetic prion diseases (gPrDs) are caused by autosomal-dominant mutations in the prion protein gene (PRNP). Although the first PRNP mutations identified, and most since, are PRNP missense, octapeptide repeat insertions, deletion and nonsense mutations have now also been shown to cause gPrD. Based on clinicopathologic features of familial disease, gPrDs historically have been classified into three forms: familial Jakob–Creutzfeldt disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. This classification, however, occurred prior to the identification of PRNP, and although these forms are still recognized, classification now is somewhat more complex. Clinical manifestations, and even pathology, are known to be more heterogeneous and varied than the historic three phenotypic classifications. Most gPrDs either present rapidly with progression of dementia, ataxia, myoclonus, and other motor features leading to death in few months or present more slowly, declining over a few years with mild cognitive impairment, ataxia, or parkinsonism and later dementia; a few very rare mutations, however, present over years to decades with neuropsychiatric disorders and systemic symptoms (gastrointestinal disorders and neuropathy). In this chapter, we review the broad phenotypic spectrum of PRNP mutations causing gPrDs.
G-quadruplexes: Emerging roles in neurodegenerative diseases and the non-coding transcriptome
2015, FEBS Letters
G-rich sequences in DNA and RNA have a propensity to fold into stable secondary structures termed G-quadruplexes. G-quadruplex forming sequences are widespread throughout the human genome, within both, protein coding and non-coding genes, and regulatory regions. G-quadruplexes have been implicated in multiple cellular functions including chromatin epigenetic regulation, DNA recombination, transcriptional regulation of gene promoters and enhancers, and translation. Here we will review the evidence for the occurrence of G-quadruplexes both in vitro and in vivo; their role in neurological diseases including G-quadruplex-forming repeat expansions in the C9orf72 gene in frontotemporal dementia and amyotrophic lateral sclerosis and loss of the G-quadruplex binding protein FMRP in the intellectual disability fragile X syndrome. We also review mounting evidence that supports a role for G-quadruplexes in regulating the processing or function of a range of non-coding RNAs. Finally we will highlight current perspectives for therapeutic interventions that target G-quadruplexes.
Cobalamin (vitamin B <inf>12</inf>) regulation of PrP <sup>C</sup>, PrP <sup>C</sup>-mRNA and copper levels in rat central nervous system
2012, Experimental Neurology
Citation Excerpt :
To the best of our knowledge, this is the first demonstration of an experimental SC myelin disease caused by a local excess of the OR region. Too many OR regions (as in Cbl deficiency, some human prion diseases (Owen et al., 1992; Krasemann et al., 1995; Mead, 2006; Mead et al., 2007), and Tg(PG14) mice (Chiesa and Harris, 2001)) are as deleterious for CNS myelin as none (as in OR knock-out mice (Baumann et al., 2007; Mitteregger et al., 2007)). It is therefore conceivable that the number of OR regions in rat SC is “buffered” by still unknown mechanisms in order to keep the myelin normal, and that Cbl plays a key role in this.
The pathogenesis of cobalamin (Cbl)-deficient (Cbl-D) neuropathy is not clear, nor is the role of prions (PrP^C) in myelin maintenance. However, as it is known that Cbl deficiency damages myelin by increasing tumor necrosis factor (TNF)-α and decreasing epidermal growth factor (EGF) levels in rat spinal cord (SC), and that TNF-α and EGF regulate PrP^C expression in vitro, we investigated whether Cbl deficiency modifies SC PrP^C and PrP^C-mRNA levels in Cbl-D rats. PrP^C levels had increased by the time myelin lesions appeared. This increase was mediated by excess myelinotoxic TNF-α and prevented by EGF, which proved to be as effective as Cbl in preventing Cbl deficiency-induced lesions. There were no significant changes in hepatic PrP^C levels of Cbl-D rats. Anti-octapeptide repeat (OR) region antibodies normalized SC myelin morphology. Cbl deficiency greatly reduced SC PrP^C-mRNA levels, which were subsequently increased by Cbl and EGF. Cbl deficiency-induced excess OR is myelin-damaging, but new PrP^C synthesis is a common effect of different myelinotrophic agents.
Infectious prion protein alters manganese transport and neurotoxicity in a cell culture model of prion disease
2011, NeuroToxicology
Citation Excerpt :
PrPC contains multiple octapeptide repeat sequences (PHGGSWGQ) toward the N-terminus that have binding affinity for various divalent metals including copper and manganese (Hornshaw et al., 1995; Viles et al., 1999). The number of octapeptide repeats differs from species to species; however, point mutations, deletions or multiple insertions of the octapeptide repeats in the prion protein gene have been linked to inherited prion disease in humans (Krasemann et al., 1995; Mead et al., 2007; Palmer and Collinge, 1993; Yin et al., 2007). Structural studies have suggested that most of the N-terminus of prion protein is rather unstructured, while the C-terminus is highly structured (Di Natale et al., 2005; Jones et al., 2005; Renner et al., 2004; Viles et al., 2001).
Protein misfolding and aggregation are considered key features of many neurodegenerative diseases, but biochemical mechanisms underlying protein misfolding and the propagation of protein aggregates are not well understood. Prion disease is a classical neurodegenerative disorder resulting from the misfolding of endogenously expressed normal cellular prion protein (PrP^C). Although the exact function of PrP^C has not been fully elucidated, studies have suggested that it can function as a metal binding protein. Interestingly, increased brain manganese (Mn) levels have been reported in various prion diseases indicating divalent metals also may play a role in the disease process. Recently, we reported that PrP^C protects against Mn-induced cytotoxicity in a neural cell culture model. To further understand the role of Mn in prion diseases, we examined Mn neurotoxicity in an infectious cell culture model of prion disease. Our results show CAD5 scrapie-infected cells were more resistant to Mn neurotoxicity as compared to uninfected cells (EC₅₀ = 428.8 μM for CAD5 infected cells vs. 211.6 μM for uninfected cells). Additionally, treatment with 300 μM Mn in persistently infected CAD5 cells showed a reduction in mitochondrial impairment, caspase-3 activation, and DNA fragmentation when compared to uninfected cells. Scrapie-infected cells also showed significantly reduced Mn uptake as measured by inductively coupled plasma-mass spectrometry (ICP-MS), and altered expression of metal transporting proteins DMT1 and transferrin. Together, our data indicate that conversion of PrP to the pathogenic isoform enhances its ability to regulate Mn homeostasis, and suggest that understanding the interaction of metals with disease-specific proteins may provide further insight to protein aggregation in neurodegenerative diseases.
Pooled analysis of patients with inherited prion disease caused by two- to twelve-octapeptide repeat insertions in the prion protein gene (PRNP)
2024, Journal of Neurology

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Short communicationPrion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene

Abstract

Cell

Mol. Brain Res.

Biochem. Biophys. Res. Commun.

Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay between ancient genes and modern medicine

Neurology

Diagnosis of Creutzfeldt-Jakob disease by Western blot identification of marker protein in human brain tissue

New Engl. J. Med.

Short communication
Prion disease associated with a novel nine octapeptide repeat insertion in the PRNP gene