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

Neuro–CEB Neuropathology Network

doi:10.1016/j.neuron.2020.04.011

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

Neuro–CEB Neuropathology Network

Neuroscience

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Pages (from-to)	292-305.e6
Journal	Neuron
Volume	107
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2020.04.011
State	Published - Jul 22 2020

Keywords

ALS
C9orf72 expansion
FTD
RAN translation
SCA36
antisense oligonucleotide therapy
chimeric DPRs
dipeptide repeats
neurodegeneration

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2020.04.011

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@article{e73e03c625b447369326927627b6a339,

title = "Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36",

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",

author = "{Neuro–CEB Neuropathology Network} and McEachin, {Zachary T.} and Gendron, {Tania F.} and Nisha Raj and Mar{\'i}a Garc{\'i}a-Murias and Anwesha Banerjee and Purcell, {Ryan H.} and Ward, {Patricia J.} and Todd, {Tiffany W.} and Merritt-Garza, {Megan E.} and Karen Jansen-West and Hales, {Chadwick M.} and Tania Garc{\'i}a-Sobrino and Beatriz Quint{\'a}ns and Holler, {Christopher J.} and Georgia Taylor and {San Mill{\'a}n}, Beatriz and Susana Teijeira and Toru Yamashita and Ryuichi Ohkubo and Boulis, {Nicholas M.} and Chongchong Xu and Zhexing Wen and Nathalie Streichenberger and Fogel, {Brent L.} and Thomas Kukar and Koji Abe and Dickson, {Dennis W.} and Manuel Arias and Glass, {Jonathan D.} and Jie Jiang and Tansey, {Mal{\'u} G.} and Sobrido, {Mar{\'i}a Jes{\'u}s} and Leonard Petrucelli and Wilfried Rossoll and Bassell, {Gary J.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jul,

day = "22",

doi = "10.1016/j.neuron.2020.04.011",

language = "English (US)",

volume = "107",

pages = "292--305.e6",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

AU - Neuro–CEB Neuropathology Network

AU - McEachin, Zachary T.

AU - Gendron, Tania F.

AU - Raj, Nisha

AU - García-Murias, María

AU - Banerjee, Anwesha

AU - Purcell, Ryan H.

AU - Ward, Patricia J.

AU - Todd, Tiffany W.

AU - Merritt-Garza, Megan E.

AU - Jansen-West, Karen

AU - Hales, Chadwick M.

AU - García-Sobrino, Tania

AU - Quintáns, Beatriz

AU - Holler, Christopher J.

AU - Taylor, Georgia

AU - San Millán, Beatriz

AU - Teijeira, Susana

AU - Yamashita, Toru

AU - Ohkubo, Ryuichi

AU - Boulis, Nicholas M.

AU - Xu, Chongchong

AU - Wen, Zhexing

AU - Streichenberger, Nathalie

AU - Fogel, Brent L.

AU - Kukar, Thomas

AU - Abe, Koji

AU - Dickson, Dennis W.

AU - Arias, Manuel

AU - Glass, Jonathan D.

AU - Jiang, Jie

AU - Tansey, Malú G.

AU - Sobrido, María Jesús

AU - Petrucelli, Leonard

AU - Rossoll, Wilfried

AU - Bassell, Gary J.

PY - 2020/7/22

Y1 - 2020/7/22

N2 - 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.

AB - 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.

KW - ALS

KW - C9orf72 expansion

KW - FTD

KW - RAN translation

KW - SCA36

KW - antisense oligonucleotide therapy

KW - chimeric DPRs

KW - dipeptide repeats

KW - neurodegeneration

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UR - http://www.scopus.com/inward/citedby.url?scp=85084974096&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2020.04.011

DO - 10.1016/j.neuron.2020.04.011

M3 - Article

C2 - 32375063

AN - SCOPUS:85084974096

SN - 0896-6273

VL - 107

SP - 292-305.e6

JO - Neuron

JF - Neuron

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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