Cyclic naphthyridine dimers as therapeutic agents for fragile X-associated tremor/ataxia syndrome

• Autorzy: Konieczny P. , Mukherjee S. , Dohno C. , Nakatani K. , Sobczak K.
• Języki publikacji: EN

Abstrakty

EN

INTRODUCTION: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansion of CGG trinucleotides in the 5’UTR of the FMR1 gene. The patients, with the number of the repeats ranging from 55 to 200, show specific manifestation of clinical symptoms that include intention tremor, cerebellar ataxia, neuropathic pain, parkinsonian features and cognitive deficits, with the underlying brain atrophy and white matter disease of particular regions. The mutation occurs with high frequency in women (1:150–300) and men (1:400–850), with the current estimate of 16–20% female and 40–75% male carriers to develop FXTAS after reaching 50 years of age. As of now, accumulation of the toxic, RAN translation polyglycine (polyGLY) product, expressed from the expanded CGG repeats, is considered to be the main triggering factor of neurodegenerative processes in FXTAS patients. AIM(S): We aimed at estimating if cyclic naphthyridine dimers could be used to block expression of toxic polyGLY in cells expressing transcripts carrying expanded CGG repeats. We also targeted at evaluation whether this potentially therapeutic intervention could be achieved without affecting generation of FMRP, a protein translated independently from polyGLY from the mutated FMR1 transcript. METHOD(S): We employed forced expression of plasmids carrying expanded CGG triplets and sequences coding for eGFP or luciferase cloned either in or out of frame to the repeats, to evaluate the relative expression of polyGLY and FMRP following administration of cyclic naphthyridine dimers. RESULTS: Our cell culture experiments revealed that cyclic naphthyridine dimers efficiently block expression of polyGLY without affecting the overall RNA content of transcripts carrying expanded CGG repeats. CONCLUSIONS: Cyclic naphthyridine dimers efficiently block expression of the toxic RAN translation product generated from forced expressed plasmids carrying expanded CGG repeats in cell culture experiments. FINANCIAL SUPPORT: National Centre for Research and Development grant ERA-NET-E-Rare-2/III/DRUG_FXSPREMUT/01/2016. Ministry of Science and Higher Education of the Republic of Poland, from the quality-promoting subsidy, under the Leading National Research Centre (KNOW) programme for the years 2012–2017 (KNOW RNA Research Centre in Poznan) [01/KNOW2/2014].

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.72

Twórcy

autor

Konieczny P.

• Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, Poland

autor

Mukherjee S.

• Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan

autor

Dohno C.

• Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan

autor

Nakatani K.

• Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan

autor

Sobczak K.

• Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Poznan, Poland