Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by combined systemic degeneration of the dentatofugal and pallidofugal pathways. We investigated a candidate gene and found that DRPLA patients had an expanded CAG trinucleotide repeat in a gene on the short arm of chromosome 12. The repeat size varied from 7−23 in normal individuals. In patients one allele was expanded to between 49−75 repeats or occasionally even more. Expansion was usually associated with paternal transmission and only occasionally with maternal transmission. Repeat size showed a close correlation with age of onset of symptoms and disease severity. We conclude that DRPLA is the seventh genetic disorder known to be associated with expansion of an unstable trinucleotide repeat.
[Show abstract][Hide abstract] ABSTRACT: DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion.
Published by Elsevier B.V.
DNA repair 04/2015; 32. DOI:10.1016/j.dnarep.2015.04.019 · 3.11 Impact Factor
"Molecular genetics studies on inherited neurodegenerative diseases in the last few decades have revealed a common genetic mutation shared by a group of diseases, namely, an expansion (>40) of the CAG repeat encoding a polyQ stretch in each unrelated disease-causing gene, and hence these diseases are called the polyQ diseases  . Currently nine diseases have been found to belong to this group, including Huntington's disease, spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinobulbar muscular atrophy (SBMA)            . "
[Show abstract][Hide abstract] ABSTRACT: Misfolding and abnormal aggregation of proteins in the brain are implicated in the pathogenesis of various neurodegenerative diseases including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases. In the polyQ diseases, an abnormally expanded polyQ stretch triggers misfolding and aggregation of the disease-causing proteins, eventually resulting in neurodegeneration. In this paper, we introduce our therapeutic strategy against the polyQ diseases using polyQ binding peptide 1 (QBP1), a peptide that we identified by phage display screening. We showed that QBP1 specifically binds to the expanded polyQ stretch and inhibits its misfolding and aggregation, resulting in suppression of neurodegeneration in cell culture and animal models of the polyQ diseases. We further demonstrated the potential of protein transduction domains (PTDs) for in vivo delivery of QBP1. We hope that in the near future, chemical analogues of aggregation inhibitor peptides including QBP1 will be developed against protein misfolding-associated neurodegenerative diseases.
"In 1994, we and another group, focusing on genes containing CAG repeats (3), found that DRPLA is caused by an unstable expansion of CAG repeats coding for polyglutamine (polyQ) stretches in exon 5 of the DRPLA gene on chromosome 12p13.31 (4,5). To date, polyQ expansions have been identified as the pathogenic mutations in nine neurodegenerative diseases including Huntington’s disease (HD), spinal and bulbar muscular atrophy, DRPLA and various forms of dominant spinocerebellar ataxias (SCAs) (6). "
[Show abstract][Hide abstract] ABSTRACT: We herein provide a thorough description of new transgenic mouse models for dentatorubral-pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and gamma-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions.
Human Molecular Genetics 12/2008; 18(4):723-36. DOI:10.1093/hmg/ddn403 · 6.39 Impact Factor
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