Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo

Tiffany W. Todd; Zachary T. McEachin; Jeannie Chew; Alexander R. Burch; Karen Jansen-West; Jimei Tong; Mei Yue; Yuping Song; Monica Castanedes-Casey; Aishe Kurti; Judith H. Dunmore; John D. Fryer; Yong Jie Zhang; Beatriz San Millan; Susana Teijeira Bautista; Manuel Arias; Dennis Dickson; Tania F. Gendron; María Jesús Sobrido; Matthew D. Disney; Gary J. Bassell; Wilfried Rossoll; Leonard Petrucelli

doi:10.1016/j.celrep.2020.107616

Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo

Tiffany W. Todd, Zachary T. McEachin, Jeannie Chew, Alexander R. Burch, Karen Jansen-West, Jimei Tong, Mei Yue, Yuping Song, Monica Castanedes-Casey, Aishe Kurti, Judith H. Dunmore, John D. Fryer, Yong Jie Zhang, Beatriz San Millan, Susana Teijeira Bautista, Manuel Arias, Dennis Dickson, Tania F. Gendron, María Jesús Sobrido, Matthew D. DisneyGary J. Bassell, Wilfried Rossoll, Leonard Petrucelli

Neuroscience

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

7 Scopus citations

Abstract

A G₄C₂ hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG₃C₂ repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G₄C₂ repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.

Original language	English (US)
Article number	107616
Journal	Cell reports
Volume	31
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2020.107616
State	Published - May 5 2020

Keywords

ALS
C9orf72
FTD
RAN translation
RNA foci
SCA36
TDP-43
mouse
poly(GP)
poly(PR)

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2020.107616

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Todd, T. W., McEachin, Z. T., Chew, J., Burch, A. R., Jansen-West, K., Tong, J., Yue, M., Song, Y., Castanedes-Casey, M., Kurti, A., Dunmore, J. H., Fryer, J. D., Zhang, Y. J., San Millan, B., Teijeira Bautista, S., Arias, M., Dickson, D., Gendron, T. F., Sobrido, M. J., ... Petrucelli, L. (2020). Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo. Cell reports, 31(5), Article 107616. https://doi.org/10.1016/j.celrep.2020.107616

Todd, TW, McEachin, ZT, Chew, J, Burch, AR, Jansen-West, K, Tong, J, Yue, M, Song, Y, Castanedes-Casey, M, Kurti, A, Dunmore, JH, Fryer, JD, Zhang, YJ, San Millan, B, Teijeira Bautista, S, Arias, M, Dickson, D , Gendron, TF, Sobrido, MJ, Disney, MD, Bassell, GJ, Rossoll, W & Petrucelli, L 2020, 'Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo', Cell reports, vol. 31, no. 5, 107616. https://doi.org/10.1016/j.celrep.2020.107616

@article{bbb48d0d43d3434cb1c604e326ce14e3,

title = "Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo",

abstract = "A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.",

keywords = "ALS, C9orf72, FTD, RAN translation, RNA foci, SCA36, TDP-43, mouse, poly(GP), poly(PR)",

author = "Todd, {Tiffany W.} and McEachin, {Zachary T.} and Jeannie Chew and Burch, {Alexander R.} and Karen Jansen-West and Jimei Tong and Mei Yue and Yuping Song and Monica Castanedes-Casey and Aishe Kurti and Dunmore, {Judith H.} and Fryer, {John D.} and Zhang, {Yong Jie} and {San Millan}, Beatriz and {Teijeira Bautista}, Susana and Manuel Arias and Dennis Dickson and Gendron, {Tania F.} and Sobrido, {Mar{\'i}a Jes{\'u}s} and Disney, {Matthew D.} and Bassell, {Gary J.} and Wilfried Rossoll and Leonard Petrucelli",

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year = "2020",

month = may,

day = "5",

doi = "10.1016/j.celrep.2020.107616",

language = "English (US)",

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T1 - Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo

AU - Todd, Tiffany W.

AU - McEachin, Zachary T.

AU - Chew, Jeannie

AU - Burch, Alexander R.

AU - Jansen-West, Karen

AU - Tong, Jimei

AU - Yue, Mei

AU - Song, Yuping

AU - Castanedes-Casey, Monica

AU - Kurti, Aishe

AU - Dunmore, Judith H.

AU - Fryer, John D.

AU - Zhang, Yong Jie

AU - San Millan, Beatriz

AU - Teijeira Bautista, Susana

AU - Arias, Manuel

AU - Dickson, Dennis

AU - Gendron, Tania F.

AU - Sobrido, María Jesús

AU - Disney, Matthew D.

AU - Bassell, Gary J.

AU - Rossoll, Wilfried

AU - Petrucelli, Leonard

PY - 2020/5/5

Y1 - 2020/5/5

N2 - A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.

AB - A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.

KW - ALS

KW - C9orf72

KW - FTD

KW - RAN translation

KW - RNA foci

KW - SCA36

KW - TDP-43

KW - mouse

KW - poly(GP)

KW - poly(PR)

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SN - 2211-1247

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JO - Cell reports

JF - Cell reports

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M1 - 107616

ER -

Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo

Abstract

Keywords

ASJC Scopus subject areas

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