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Congo red, doxycycline, and HSP70 overexpression reduce aggregate formation and cell death in cell models of oculopharyngeal muscular dystrophy
  1. Y P Bao1,
  2. S Sarkar1,
  3. E Uyama2,
  4. D C Rubinsztein1
  1. 1Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2XY, United Kingdom
  2. 2Department of Neurology, Kumamoto University School of Medicine, 1-1-1-Honjo, Kumamoto, 860-0811, Japan
  1. Correspondence to:
 D C Rubinsztein;

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The formation of intracellular amyloid-like inclusions by mutant proteins is a feature of two groups of codon reiteration diseases, for which there are currently no treatments. The first group that was described includes the nine known neurodegenerative conditions caused by polyglutamine (polyQ) repeat expansions resulting from CAG trinucleotide repeat mutations, exemplified by Huntington’s disease (HD).1 HD is caused by a tract of more than 37 uninterrupted polyglutamines in exon 1 of the HD gene product, huntingtin. Genetic and transgenic studies are consistent with a model where expanded polyglutamines cause disease by conferring a novel toxic function on the disease proteins.1–3

The second type of codon reiteration mutation results in autosomal dominant oculopharyngeal muscular dystrophy (OPMD).4 OPMD is caused by the abnormal expansion of a (GCG)n trinucleotide repeat in the coding region of the polyadenine binding protein 2 gene (PABP2): a (GCG)6 repeat is expanded to (GCG)8–13 in most patients. In some rare cases, insertion mutations such as (GCG)6GCA(GCG)2, (GCG)6GCA(GCG)3 and (GCG)6(GCA)3(GCG)2 are seen.5,6 In PABP2, (GCG)6 codes for the first six alanines in a homopolymeric stretch of 10 alanines. Thus, disease is associated with expansions of 12 or more uninterrupted alanines in this nuclear protein. OPMD is characterised by aggregates in muscle cell nuclei comprising mutant PABP2 as a major component.4,7–9

The role of inclusions in these diseases has been vigorously disputed.1 Nevertheless, strategies that target protein misfolding frequently reduce aggregate formation and cell death in parallel. In mammalian cell based models of both polyglutamine and polyalanine diseases, the mutant proteins are much more prone to aggregate formation than their wild-type counterparts and cause significantly more cell death.10,11 In such models, …

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  • This work was funded by the Muscular Dystrophy Campaign (UK), the MRC (Programme grant to DCR and Professor Steve Brown) and Grants-in-Aid for Scientific Research (EU) for funding. We are grateful for a Wellcome Trust Senior Fellowship in Clinical Science (DCR) and a Gates Cambridge Scholarship (SS).