Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity-Reference-Cited by-同舟云学术

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

Published:2019-02-15 Issue:6428 Volume:363 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Zhang Yong-Jie¹²^ORCID,Guo Lin³^ORCID,Gonzales Patrick K.⁴^ORCID,Gendron Tania F.¹²^ORCID,Wu Yanwei¹,Jansen-West Karen¹,O’Raw Aliesha D.¹^ORCID,Pickles Sarah R.¹^ORCID,Prudencio Mercedes¹²^ORCID,Carlomagno Yari¹^ORCID,Gachechiladze Mariam A.⁵,Ludwig Connor⁶,Tian Ruilin⁶,Chew Jeannie¹²^ORCID,DeTure Michael¹²^ORCID,Lin Wen-Lang¹,Tong Jimei¹,Daughrity Lillian M.¹^ORCID,Yue Mei¹,Song Yuping¹,Andersen Jonathan W.¹,Castanedes-Casey Monica¹^ORCID,Kurti Aishe¹,Datta Abhishek⁷,Antognetti Giovanna⁷,McCampbell Alexander⁸^ORCID,Rademakers Rosa¹²^ORCID,Oskarsson Björn⁹^ORCID,Dickson Dennis W.¹²^ORCID,Kampmann Martin⁶^ORCID,Ward Michael E.⁵^ORCID,Fryer John D.¹²,Link Christopher D.⁴,Shorter James³^ORCID,Petrucelli Leonard¹²^ORCID

Affiliation:

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.

Abstract

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606

Funder

National Institute on Aging

National Institute of General Medical Sciences

National Institute of Neurological Disorders and Stroke

Amyotrophic Lateral Sclerosis Association

Mayo Clinic Foundation

Target ALS Foundation

Robert Packard Center for ALS Research at Johns Hopkins

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary