ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD

Stephen Moore, Eric Alsop, Ileana Lorenzini, Alexander Starr, Benjamin E. Rabichow, Emily Mendez, Jennifer L. Levy, Camelia Burciu, Rebecca Reiman, Jeannie Chew, Veronique Belzil, Dennis W. Dickson, Janice Robertson, Kim A. Staats, Justin K. Ichida, Leonard Petrucelli, Kendall Van Keuren-Jensen, Rita Sattler

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The hexanucleotide repeat expansion GGGGCC (G 4 C 2 ) n in the C9orf72 gene is the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent findings suggest that dysfunction of nuclear-cytoplasmic trafficking could affect the transport of RNA binding proteins in C9orf72 ALS/FTD. Here, we provide evidence that the RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is mislocalized in C9orf72 repeat expansion mediated ALS/FTD. ADAR2 is responsible for adenosine (A) to inosine (I) editing of double-stranded RNA, and its function has been shown to be essential for survival. Here we show the mislocalization of ADAR2 in human induced pluripotent stem cell-derived motor neurons (hiPSC-MNs) from C9orf72 patients, in mice expressing (G 4 C 2 ) 149 , and in C9orf72 ALS/FTD patient postmortem tissue. As a consequence of this mislocalization we observe alterations in RNA editing in our model systems and across multiple brain regions. Analysis of editing at 408,580 known RNA editing sites indicates that there are vast RNA A to I editing aberrations in C9orf72-mediated ALS/FTD. These RNA editing aberrations are found in many cellular pathways, such as the ALS pathway and the crucial EIF2 signaling pathway. Our findings suggest that the mislocalization of ADAR2 in C9orf72 mediated ALS/FTD is responsible for the alteration of RNA processing events that may impact vast cellular functions, including the integrated stress response (ISR) and protein translation.

Original languageEnglish (US)
JournalActa neuropathologica
DOIs
StatePublished - Jan 1 2019

Fingerprint

RNA Editing
Adenosine Deaminase
RNA
Amyotrophic Lateral Sclerosis
Eukaryotic Initiation Factor-2
Induced Pluripotent Stem Cells
Inosine
RNA-Binding Proteins
Double-Stranded RNA
Protein Biosynthesis
Motor Neurons
Heat-Shock Proteins
Adenosine
Frontotemporal Dementia With Motor Neuron Disease
Survival
Brain
Enzymes
Genes

Keywords

  • ADAR2
  • ALS
  • C9orf72
  • FTD
  • iPSC neurons
  • Neurodegeneration
  • Nucleocytoplasmic mislocalization
  • Protein accumulation
  • RNA editing
  • RNA metabolism
  • RNA-seq

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Moore, S., Alsop, E., Lorenzini, I., Starr, A., Rabichow, B. E., Mendez, E., ... Sattler, R. (2019). ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD. Acta neuropathologica. https://doi.org/10.1007/s00401-019-01999-w

ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD. / Moore, Stephen; Alsop, Eric; Lorenzini, Ileana; Starr, Alexander; Rabichow, Benjamin E.; Mendez, Emily; Levy, Jennifer L.; Burciu, Camelia; Reiman, Rebecca; Chew, Jeannie; Belzil, Veronique; W. Dickson, Dennis; Robertson, Janice; Staats, Kim A.; Ichida, Justin K.; Petrucelli, Leonard; Van Keuren-Jensen, Kendall; Sattler, Rita.

In: Acta neuropathologica, 01.01.2019.

Research output: Contribution to journalArticle

Moore, S, Alsop, E, Lorenzini, I, Starr, A, Rabichow, BE, Mendez, E, Levy, JL, Burciu, C, Reiman, R, Chew, J, Belzil, V, W. Dickson, D, Robertson, J, Staats, KA, Ichida, JK, Petrucelli, L, Van Keuren-Jensen, K & Sattler, R 2019, 'ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD', Acta neuropathologica. https://doi.org/10.1007/s00401-019-01999-w
Moore, Stephen ; Alsop, Eric ; Lorenzini, Ileana ; Starr, Alexander ; Rabichow, Benjamin E. ; Mendez, Emily ; Levy, Jennifer L. ; Burciu, Camelia ; Reiman, Rebecca ; Chew, Jeannie ; Belzil, Veronique ; W. Dickson, Dennis ; Robertson, Janice ; Staats, Kim A. ; Ichida, Justin K. ; Petrucelli, Leonard ; Van Keuren-Jensen, Kendall ; Sattler, Rita. / ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD. In: Acta neuropathologica. 2019.
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