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Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

Prudencio, Mercedes (author)
Mayo Clinic Florida
Garcia-Moreno, Hector (author)
Jansen-West, Karen R (author)
University of Geneva
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Al-Shaikh, Rana Hanna (author)
Nordsjællands Hospital
Gendron, Tania F (author)
University of Geneva
Heckman, Michael G (author)
Mayo Clinic Minnesota
Spiegel, Matthew R (author)
Mayo Clinic Minnesota
Carlomagno, Yari (author)
University of Geneva
Daughrity, Lillian M (author)
University of Geneva
Song, Yuping (author)
University of Geneva
Dunmore, Judith A (author)
University of Geneva
Byron, Natalie (author)
University of Geneva
Oskarsson, Björn (author)
Nordsjællands Hospital
Nicholson, Katharine A (author)
Staff, Nathan P (author)
Nordsjællands Hospital
Gorcenco, Sorina (author)
Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Skåne University Hospital
Puschmann, Andreas (author)
Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Skåne University Hospital
Lemos, João (author)
Center for Neuroscience and Cell Biology, University of Coimbra
Januário, Cristina (author)
Center for Neuroscience and Cell Biology, University of Coimbra
LeDoux, Mark S (author)
Friedman, Joseph H (author)
Polke, James (author)
Labrum, Robin (author)
Shakkottai, Vikram (author)
Western Michigan University
McLoughlin, Hayley S (author)
Western Michigan University
Paulson, Henry L (author)
Western Michigan University
Konno, Takuya (author)
Niigata University
Onodera, Osamu (author)
Niigata University
Ikeuchi, Takeshi (author)
Niigata University
Tada, Mari (author)
Niigata University
Kakita, Akiyoshi (author)
Niigata University
Fryer, John D (author)
Karremo, Christin (author)
Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Skåne University Hospital
Gomes, Inês (author)
Center for Neuroscience and Cell Biology, University of Coimbra
Caviness, John N (author)
Nordsjællands Hospital
Pittelkow, Mark R (author)
Aasly, Jan (author)
Norwegian University of Science and Technology
Pfeiffer, Ronald F (author)
Oregon Health & Science University
Veerappan, Venka (author)
Oregon Health & Science University
Eggenberger, Eric R (author)
Nordsjællands Hospital
Freeman, William D (author)
Nordsjællands Hospital
Huang, Josephine F (author)
Nordsjællands Hospital
Uitti, Ryan J (author)
Nordsjællands Hospital
Wierenga, Klaas J (author)
Nordsjællands Hospital
Marin Collazo, Iris V (author)
Nordsjællands Hospital
Tipton, Philip W (author)
Nordsjællands Hospital
van Gerpen, Jay A (author)
University of South Alabama
van Blitterswijk, Marka (author)
University of Geneva
Bu, Guojun (author)
University of Geneva
Wszolek, Zbigniew K (author)
Nordsjællands Hospital
Petrucelli, Leonard (author)
Mayo Clinic Florida
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 (creator_code:org_t)
et al 
American Association for the Advancement of Science (AAAS), 2020
2020
English.
In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:566
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

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art (subject category)
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