RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2

Tao Zu; John D Cleary; Yuanjing Liu; Monica Bañez-Coronel; Jodi L Bubenik; Fatma Ayhan; Tetsuo Ashizawa; Guangbin Xia; H Brent Clark; Anthony T Yachnis; Maurice S Swanson; Laura P W Ranum

doi:10.1016/j.neuron.2017.08.039

RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2

Neuron. 2017 Sep 13;95(6):1292-1305.e5. doi: 10.1016/j.neuron.2017.08.039.

Authors

Affiliations

¹ Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
² Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA; Neurological Institute, Houston Methodist Hospital, Houston, TX 77030, USA.
³ Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
⁴ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁵ Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
⁶ Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA; Genetics Institute, University of Florida, Gainesville, FL 32610, USA.
⁷ Center for NeuroGenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, University of Florida, Gainesville, FL 32610, USA; Genetics Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: ranum@ufl.edu.

Abstract

Several microsatellite-expansion diseases are characterized by the accumulation of RNA foci and RAN proteins, raising the possibility of a mechanistic connection. We explored this question using myotonic dystrophy type 2, a multisystemic disease thought to be primarily caused by RNA gain-of-function effects. We demonstrate that the DM2 CCTG⋅CAGG expansion expresses sense and antisense tetrapeptide poly-(LPAC) and poly-(QAGR) RAN proteins, respectively. In DM2 autopsy brains, LPAC is found in neurons, astrocytes, and glia in gray matter, and antisense QAGR proteins accumulate within white matter. LPAC and QAGR proteins are toxic to cells independent of RNA gain of function. RNA foci and nuclear sequestration of CCUG transcripts by MBNL1 is inversely correlated with LPAC expression. These data suggest a model that involves nuclear retention of expansion RNAs by RNA-binding proteins (RBPs) and an acute phase in which expansion RNAs exceed RBP sequestration capacity, are exported to the cytoplasm, and undergo RAN translation. VIDEO ABSTRACT.

Keywords: C9ORF72; DM; DM2; MBNL; RAN translation; RNA foci; muscleblind proteins; myotonic dystrophy; non-ATG translation; non-AUG initiation.

Publication types

Video-Audio Media

MeSH terms

Brain / metabolism
Cell Survival
Cells, Cultured
Gene Expression Regulation
Humans
Mutation
Myotonic Dystrophy / metabolism*
Protein Biosynthesis*
RNA / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
ran GTP-Binding Protein / biosynthesis*
ran GTP-Binding Protein / toxicity

Substances

CNBP protein, human
MBNL1 protein, human
RNA-Binding Proteins
RNA
ran GTP-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding