University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Neurology; Department of Psychiatry

Date

9-2013

Document Type

Article

Medical Subject Headings

Amyotrophic Lateral Sclerosis; Animals; Cell Differentiation; DNA Repeat Expansion; Frontotemporal Dementia; Genotype; Humans; Induced Pluripotent Stem Cells; Mice; Mutation; Neurons; Proteins; RNA-Binding Proteins

Disciplines

Medical Pathology | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology | Pathological Conditions, Signs and Symptoms | Psychiatry

Abstract

The recently identified GGGGCC repeat expansion in the noncoding region of C9ORF72 is the most common pathogenic mutation in patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS). We generated a human neuronal model and investigated the pathological phenotypes of human neurons containing GGGGCC repeat expansions. Skin biopsies were obtained from two subjects who had > 1,000 GGGGCC repeats in C9ORF72 and their respective fibroblasts were used to generate multiple induced pluripotent stem cell (iPSC) lines. After extensive characterization, two iPSC lines from each subject were selected, differentiated into postmitotic neurons, and compared with control neurons to identify disease-relevant phenotypes. Expanded GGGGCC repeats exhibit instability during reprogramming and neuronal differentiation of iPSCs. RNA foci containing GGGGCC repeats were present in some iPSCs, iPSC-derived human neurons and primary fibroblasts. The percentage of cells with foci and the number of foci per cell appeared to be determined not simply by repeat length but also by other factors. These RNA foci do not seem to sequester several major RNA-binding proteins. Moreover, repeat-associated non-ATG (RAN) translation products were detected in human neurons with GGGGCC repeat expansions and these neurons showed significantly elevated p62 levels and increased sensitivity to cellular stress induced by autophagy inhibitors. Our findings demonstrate that key neuropathological features of FTD/ALS with GGGGCC repeat expansions can be recapitulated in iPSC-derived human neurons and also suggest that compromised autophagy function may represent a novel underlying pathogenic mechanism.

Rights and Permissions

Citation: Acta Neuropathol. 2013 Sep;126(3):385-99. doi: 10.1007/s00401-013-1149-y. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Keywords

ALS, Autophagy, C9ORF72, FTD, Hexanucleotide repeats, iPSCs, Neurodegeneration, Neurons, p62, RAN translation, RNA foci

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

 
 

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