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RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats.

Nicholas Liao

Nat Neurosci. 2019 Sep;22(9):1383-1388. doi: 10.1038/s41593-019-0455-7. | PubMed

Shizuka B Yamada1,2, Tania F Gendron3, Teresa Niccoli4,5,6, Naomi R Genuth1,2,7, Rosslyn Grosely8, Yingxiao Shi9, Idoia Glaria4,5, Nicholas J Kramer1,10, Lisa Nakayama1, Shirleen Fang1, Tai J I Dinger1,2, Annora Thoeng4,5,6, Gabriel Rocha9, Maria Barna1,7, Joseph D Puglisi8, Linda Partridge6, Justin K Ichida9, Adrian M Isaacs4,5, Leonard Petrucelli3, Aaron D Gitler11

  1. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  2. Department of Biology, Stanford University, Stanford, CA, USA.
  3. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  4. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
  5. UK Dementia Research Institute at UCL, UCL Institute of Neurology, London, UK.
  6. Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, UK.
  7. Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
  8. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
  9. Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA.
  10. Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
  11. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. agitler@stanford.edu.

Abstract

Nucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. Unconventional translation (RAN translation) of C9orf72 repeats generates dipeptide repeat proteins that can cause neurodegeneration. We performed a genetic screen for regulators of RAN translation and identified small ribosomal protein subunit 25 (RPS25), presenting a potential therapeutic target for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia and other neurodegenerative diseases caused by nucleotide repeat expansions.

Presented by Shizuka Yamada