Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

Zachary T McEachin; Tania F Gendron; Nisha Raj; María García-Murias; Anwesha Banerjee; Ryan H Purcell; Patricia J Ward; Tiffany W Todd; Megan E Merritt-Garza; Karen Jansen-West; Chadwick M Hales; Tania García-Sobrino; Beatriz Quintáns; Christopher J Holler; Georgia Taylor; Beatriz San Millán; Susana Teijeira; Toru Yamashita; Ryuichi Ohkubo; Nicholas M Boulis; Chongchong Xu; Zhexing Wen; Nathalie Streichenberger; Neuro–CEB Neuropathology Network; Brent L Fogel; Thomas Kukar; Koji Abe; Dennis W Dickson; Manuel Arias; Jonathan D Glass; Jie Jiang; Malú G Tansey; María-Jesús Sobrido; Leonard Petrucelli; Wilfried Rossoll; Gary J Bassell

doi:10.1016/j.neuron.2020.04.011

Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

Neuron. 2020 Jul 22;107(2):292-305.e6. doi: 10.1016/j.neuron.2020.04.011. Epub 2020 May 5.

Authors

Zachary T McEachin¹, Tania F Gendron², Nisha Raj³, María García-Murias⁴, Anwesha Banerjee⁵, Ryan H Purcell³, Patricia J Ward⁵, Tiffany W Todd⁶, Megan E Merritt-Garza⁷, Karen Jansen-West⁶, Chadwick M Hales⁸, Tania García-Sobrino⁹, Beatriz Quintáns⁴, Christopher J Holler¹⁰, Georgia Taylor¹⁰, Beatriz San Millán¹¹, Susana Teijeira¹¹, Toru Yamashita¹², Ryuichi Ohkubo¹³, Nicholas M Boulis¹⁴, Chongchong Xu¹⁵, Zhexing Wen¹⁶, Nathalie Streichenberger¹⁷; Neuro–CEB Neuropathology Network; Brent L Fogel¹⁸, Thomas Kukar¹⁹, Koji Abe¹², Dennis W Dickson⁶, Manuel Arias²⁰, Jonathan D Glass⁸, Jie Jiang⁵, Malú G Tansey²¹, María-Jesús Sobrido⁴, Leonard Petrucelli², Wilfried Rossoll², Gary J Bassell²²

Affiliations

¹ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA. Electronic address: zmceach@emory.edu.
² Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
³ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁴ Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
⁵ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
⁷ Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁸ Department of Neurology, Emory University, Atlanta, GA 30322, USA.
⁹ Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
¹⁰ Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
¹¹ Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; Pathology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain.
¹² Department of Neurology, Okayama University, Okayama, Japan.
¹³ Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.
¹⁴ Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA.
¹⁵ Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
¹⁶ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
¹⁷ Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon, Lyon, France; Institut NeuroMyogène CNRS UMR 5310.
¹⁸ Department of Neurology & Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹⁹ Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
²⁰ Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain; Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
²¹ Department of Neuroscience, University of Florida, Gainesville, FL 32607, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32607, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32607, USA.
²² Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA. Electronic address: gbassel@emory.edu.

Abstract

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.

Keywords: ALS; C9orf72 expansion; FTD; RAN translation; SCA36; antisense oligonucleotide therapy; chimeric DPRs; dipeptide repeats; neurodegeneration.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Amyotrophic Lateral Sclerosis / genetics*
Animals
Animals, Newborn
Antisense Elements (Genetics) / genetics
C9orf72 Protein / genetics*
DNA Repeat Expansion
Dipeptides / genetics*
Female
Frontotemporal Dementia / genetics*
Humans
Introns / genetics
Mice
Mice, Inbred C57BL
Mutant Chimeric Proteins / genetics*
Pregnancy
Repetitive Sequences, Nucleic Acid
Spinocerebellar Ataxias / genetics*

Substances

Antisense Elements (Genetics)
C9orf72 Protein
C9orf72 protein, human
Dipeptides
Mutant Chimeric Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding