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1.
Arch Biochem Biophys ; 716: 109113, 2022 02 15.
Article in English | MEDLINE | ID: mdl-34958750

ABSTRACT

All proteins have the inherent ability to undergo transformation from their native structure to a ß sheet rich fibrillar structure, called amyloid when subjected to specific conditions. Proteins with a high propensity to form amyloid fibrils have been implicated in a variety of disorders like Alzheimer's disease, Parkinson's disease, Type II diabetes, Amyotrophic Lateral Sclerosis (ALS) and prion diseases. Among the various critical factors that modulate the process of amyloid formation, disulfide bonds have been identified as one of the key determinants of amyloid propensity in proteins. Studies have shown that intra-molecular disulfide bonds impart stability to the native structure of a protein and decrease the tendency for amyloid aggregation, whereas intermolecular disulfide bonds aid in the process of aggregation. In this review, we will analyze the varying effects of both intra as well as inter-molecular disulfide bonds on the amyloid aggregation propensities of a few proteins associated with amyloid disorders.


Subject(s)
Amyloidogenic Proteins/chemistry , Amyloidosis/etiology , Disulfides/chemistry , Alzheimer Disease/etiology , Amyloidogenic Proteins/metabolism , Amyotrophic Lateral Sclerosis/etiology , Diabetes Mellitus, Type 2/etiology , Disulfides/metabolism , Humans , Insulin/chemistry , Intramolecular Lyases/chemistry , Models, Molecular , Phosphatidylinositols/metabolism , Prion Diseases/ethnology , Protein Aggregates , Protein Binding , Protein Conformation , Structure-Activity Relationship
3.
Int J Neurosci ; 120(7): 496-501, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20583902

ABSTRACT

Prion diseases are a group of etiologically heterogeneous neurodegenerative disorders. We have analyzed the coding region of PRNP gene in 121 healthy citizens of Serbia to determine whether the frequencies of M129V, E219K, and octapeptide repeat number polymorphism. For Serbian population, polymorphism of PRNP gene at codon 129 does not differ from healthy European populations. Also codon 219 is monomorphic for the Glu allele both in Serbian population and other European populations. On the contrary, in Serbian population we did not detect any deletions or insertions in octapeptide repeat region, whereas deletions were detected in other European populations.


Subject(s)
Polymorphism, Genetic/genetics , Prions/genetics , Amino Acid Substitution/genetics , Female , Genetic Predisposition to Disease/ethnology , Genetic Predisposition to Disease/genetics , Genetic Testing , Glutamic Acid/genetics , Humans , Lysine/genetics , Male , Mutagenesis, Insertional , Oligopeptides/genetics , Prion Diseases/ethnology , Prion Diseases/genetics , Prion Proteins , Repetitive Sequences, Amino Acid/genetics , Sequence Deletion/genetics , Serbia/ethnology
4.
Neurology ; 69(8): 730-8, 2007 Aug 21.
Article in English | MEDLINE | ID: mdl-17709704

ABSTRACT

BACKGROUND: Human prion diseases have sporadic, acquired and inherited etiologies and show considerable phenotypic heterogeneity. An individual inherited prion disease offers an opportunity to study the determinants of this clinicopathologic heterogeneity among individuals with the same causal mutation. METHODS: We report clinical and pathologic data from three families with different 5-octapeptide repeat insertion (5-OPRI) mutations of the prion protein gene (PRNP), extending the reported phenotypic range of this mutation. RESULTS: The proband of a South African family presented with a rapidly progressive dementia and atypical pathology associated with kuru-like prion protein plaques. The original mutation in this family probably occurred on a PRNP allele encoding a 1-octapeptide repeat deletion polymorphism. This has not been previously reported as a precursor allele in over 30 other OPRI mutation kindreds. An English family with a genetically distinct mutation but identical protein product showed clinical onsets that varied 30 years between father and daughter, an effect that may be explained by their genotypes at PRNP codon 129. A patient from Northern Ireland with a phenotype of sporadic Creutzfeldt-Jakob disease presenting with visual disturbance was unexpectedly found to have a 5-OPRI. CONCLUSIONS: When these cases were combined with the existing world literature, the mean age at onset for patients with 5-octapeptide repeat insertion (5-OPRI) was significantly later than that for patients with 6-OPRI, but both mutations exhibit a similar powerful disease modifying effect of PRNP codon 129.


Subject(s)
Genetic Predisposition to Disease/genetics , Mutation/genetics , Prion Diseases/genetics , Prions/genetics , Repetitive Sequences, Amino Acid/genetics , Adult , Codon/genetics , DNA Mutational Analysis , Disease Progression , Female , Genetic Testing , Genotype , Humans , Male , Middle Aged , Northern Ireland , Pedigree , Phenotype , Polymorphism, Genetic/genetics , Prion Diseases/ethnology , Prion Diseases/metabolism , South Africa
5.
Eur J Epidemiol ; 22(4): 257-61, 2007.
Article in English | MEDLINE | ID: mdl-17410475

ABSTRACT

Prion diseases compass transmissible spongiform neurodegenerative diseases from various causes, including the genetic and infectious ones. We investigated the prevalence of codon 117, 129 and 171 polymorphism in prion protein (PrP) in Taiwanese, mainly for the sake of the informative absence of this genetic distribution. Our subjects were 419 aged ones of Han ethic origin. We evaluated the PrP gene (PRNP) polymorphism by restriction fragment length polymorphism, after amplification of their genomic DNAs by polymerase chain reactions with specific primers, digested by restriction enzyme PvuII (for codon 117), NspI (for codon 129), and BbvI (for codon 171), respectively, and confirmed by nucleotide sequencing. All of the subjects were homozygotes at codon 117 (Ala/Ala, gca/gca) and 171 (Asn/Asn, aac/aac). There were no valine homozygotes (Val/Val) in our 419 subjects, and nine subjects (2.1%) showed methionine-valine heterozygosity (Mal/Val, atg/gtg). The methionine homozygotes (Met/Met) comprised the major population (97.9%), and the prevalence of distribution is different to that seen in Caucasians. The almost 100% conservation of the domain from codon 117 to 171 implies the warranty of PrP in cellular functions. The high prevalence of Met/Met alleles in Taiwan did not imply an increased risk of CJD, and the genetic susceptibility of CJD by codon 129 of PrP may be still elusive for the infectivity.


Subject(s)
Codon/genetics , Polymorphism, Restriction Fragment Length , Prion Diseases/genetics , Prions/genetics , Aged , Aged, 80 and over , Asian People/genetics , Developed Countries , Female , Humans , Male , Middle Aged , Polymerase Chain Reaction , Prion Diseases/ethnology , Taiwan
6.
Neurology ; 65(10): 1666-9, 2005 Nov 22.
Article in English | MEDLINE | ID: mdl-16301504

ABSTRACT

The authors performed analysis of the prion protein gene (PRNP) in 27 out of 109 confirmed prion disease patients between 1994 and 2004. E200K mutation was found in 17 cases. Another 10 patients, lacking PRNP analysis, showed positive family history. The mean annual incidence (0.27/million) and proportion (25.6%) of genetic prion disease is unusually high in Hungary and might be related to the migration of ancestors from the Slovakian focus.


Subject(s)
Amyloid/genetics , Genetic Predisposition to Disease/genetics , Mutation/genetics , Prion Diseases/epidemiology , Prion Diseases/genetics , Protein Precursors/genetics , Adult , Aged , Brain/pathology , Brain/physiopathology , Cohort Studies , DNA Mutational Analysis , Female , Genetic Predisposition to Disease/ethnology , Genetic Testing , Humans , Hungary/epidemiology , Incidence , Male , Middle Aged , Prion Diseases/ethnology , Prion Proteins , Prions , Retrospective Studies , Risk Factors , Slovakia/ethnology
7.
Neurology ; 49(2): 552-8, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9270595

ABSTRACT

Fatal familial insomnia (FFI) is an inherited prion disease characterized by progressive insomnia and dysautonomia with only modest cognitive impairment early in the disease, associated with atrophy and gliosis in the medial thalamus, but without spongiform change. FFI is associated with an aspartic acid to asparagine mutation at codon 178 of the PrP gene (D178N) in conjunction with methionine at the codon 129 polymorphic site on the mutant allele (cis-129M). We report a pedigree with this genotype in which marked clinicopathologic phenotypic heterogeneity occurred including typical Creutzfeldt-Jakob disease, FFI, and what was thought to be an autosomal dominant cerebellar ataxia (ADCA)-like-illness, suggesting that the genotype-phenotype correlation is not as tight for this mutation as is frequently supposed.


Subject(s)
Mutation , Prion Diseases/ethnology , Prion Diseases/genetics , Prions/genetics , Adult , Australia/ethnology , Brain/pathology , Female , Humans , Ireland/ethnology , Male , Middle Aged , Pedigree , Phenotype , Prion Diseases/pathology
8.
Mol Neurobiol ; 8(1): 1-13, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8086124

ABSTRACT

The unconventional viruses of the transmissible subacute spongiform encephalopathies (kuru-CJD-GSS-FFI-scrapie-BSE) are nucleants spontaneously generated from host precursor proteins altered to beta-pleated sheet configuration that polymerize into insoluble infectious amyloid fibrils. The de novo conversion to infectious amyloids is facilitated or accelerated by many different point mutations causing amino acid changes, a stop codon, or octapeptide inserts that increase the likelihood of spontaneous conversion to infectious configuration by many orders of magnitude. Similar nucleating induction of configurational change to amyloid probably occurs in other amyloidoses of brain and in systemic amyloidoses. Thus, all amyloids, particularly so-called fibrillar amyloid enhancing factors, may be considered to be infectious scrapie-like agents. These events probably occur extracellularly, thus we are attempting to reproduce them in vitro, even from synthetic polypeptides.


Subject(s)
Amyloid/metabolism , Amyloidosis/metabolism , Prion Diseases/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid/chemistry , Amyloid/genetics , Amyloid Neuropathies/genetics , Amyloid Neuropathies/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Amyloidosis/genetics , DNA Mutational Analysis , Ethnicity/genetics , Genes , Genetic Predisposition to Disease , Global Health , Humans , Incidence , Point Mutation , Polymers , Prealbumin/genetics , Prealbumin/metabolism , Prion Diseases/epidemiology , Prion Diseases/ethnology , Prion Diseases/genetics , Prion Diseases/transmission , Protein Folding , Protein Processing, Post-Translational , Protein Structure, Secondary
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