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Science. 2019 Feb 15;363(6428). pii: eaav2606. doi: 10.1126/science.aav2606.

Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
2
Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA.
3
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
5
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
6
Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, and Chan Zuckerberg Biohub, San Francisco, CA, USA.
7
Protein Chemistry, Biogen Idec, Cambridge, MA, USA.
8
Neurology Research, Biogen Idec, Cambridge, MA, USA.
9
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
10
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. petrucelli.leonard@mayo.edu.

Abstract

How hexanucleotide GGGGCC (G4C2) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G4C2 repeats. The expression of green fluorescent protein-conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, and caused heterochromatin protein 1α (HP1α) liquid-phase disruptions, decreases in HP1α expression, abnormal histone methylation, and nuclear lamina invaginations. These aberrations of histone methylation, lamins, and HP1α, which regulate heterochromatin structure and gene expression, were accompanied by repetitive element expression and double-stranded RNA accumulation. Thus, we uncovered mechanisms by which poly(PR) may contribute to the pathogenesis of C9orf72-associated FTD and ALS.

PMID:
30765536
DOI:
10.1126/science.aav2606

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