Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31

Taro Ishiguro; Nozomu Sato; Morio Ueyama; Nobuhiro Fujikake; Chantal Sellier; Akemi Kanegami; Eiichi Tokuda; Bita Zamiri; Terence Gall-Duncan; Mila Mirceta; Yoshiaki Furukawa; Takanori Yokota; Keiji Wada; J. Paul Taylor; Christopher E. Pearson; Nicolas Charlet-Berguerand; Hidehiro Mizusawa; Yoshitaka Nagai; Kinya Ishikawa

doi:10.1016/j.neuron.2017.02.046

Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31

Taro Ishiguro, Nozomu Sato, Morio Ueyama, Nobuhiro Fujikake, Chantal Sellier, Akemi Kanegami, Eiichi Tokuda, Bita Zamiri, Terence Gall-Duncan, Mila Mirceta, Yoshiaki Furukawa, Takanori Yokota, Keiji Wada, J. Paul Taylor, Christopher E. Pearson, Nicolas Charlet-Berguerand, Hidehiro Mizusawa, Yoshitaka Nagai, Kinya Ishikawa

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

98 Citations (Scopus)

Abstract

Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAA_exp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAA_exp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAA_exp. These RBPs suppress UGGAA_exp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAA_exp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.

Original language	English
Pages (from-to)	108-124.e7
Journal	Neuron
Volume	94
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2017.02.046
Publication status	Published - 5 Apr 2017
Externally published	Yes

Keywords

ALS
Drosophila melanogaster
RAN translation
RNA chaperone
RNA foci
SCA31
TDP-43
microsatellite repeat expansion diseases
ribonucleoprotein

Access to Document

10.1016/j.neuron.2017.02.046

Cite this

Ishiguro, T., Sato, N., Ueyama, M., Fujikake, N., Sellier, C., Kanegami, A., Tokuda, E., Zamiri, B., Gall-Duncan, T., Mirceta, M., Furukawa, Y., Yokota, T., Wada, K., Taylor, J. P., Pearson, C. E., Charlet-Berguerand, N., Mizusawa, H., Nagai, Y., & Ishikawa, K. (2017). Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31. Neuron, 94(1), 108-124.e7. https://doi.org/10.1016/j.neuron.2017.02.046

@article{a653d511e83a4fc585b05209ed82c320,

title = "Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31",

abstract = "Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.",

keywords = "ALS, Drosophila melanogaster, RAN translation, RNA chaperone, RNA foci, SCA31, TDP-43, microsatellite repeat expansion diseases, ribonucleoprotein",

author = "Taro Ishiguro and Nozomu Sato and Morio Ueyama and Nobuhiro Fujikake and Chantal Sellier and Akemi Kanegami and Eiichi Tokuda and Bita Zamiri and Terence Gall-Duncan and Mila Mirceta and Yoshiaki Furukawa and Takanori Yokota and Keiji Wada and Taylor, {J. Paul} and Pearson, {Christopher E.} and Nicolas Charlet-Berguerand and Hidehiro Mizusawa and Yoshitaka Nagai and Kinya Ishikawa",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = apr,

day = "5",

doi = "10.1016/j.neuron.2017.02.046",

language = "English",

volume = "94",

pages = "108--124.e7",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "1",

}

Ishiguro, T, Sato, N, Ueyama, M, Fujikake, N, Sellier, C, Kanegami, A, Tokuda, E, Zamiri, B, Gall-Duncan, T, Mirceta, M, Furukawa, Y, Yokota, T, Wada, K, Taylor, JP, Pearson, CE, Charlet-Berguerand, N, Mizusawa, H, Nagai, Y & Ishikawa, K 2017, 'Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31', Neuron, vol. 94, no. 1, pp. 108-124.e7. https://doi.org/10.1016/j.neuron.2017.02.046

TY - JOUR

T1 - Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31

AU - Ishiguro, Taro

AU - Sato, Nozomu

AU - Ueyama, Morio

AU - Fujikake, Nobuhiro

AU - Sellier, Chantal

AU - Kanegami, Akemi

AU - Tokuda, Eiichi

AU - Zamiri, Bita

AU - Gall-Duncan, Terence

AU - Mirceta, Mila

AU - Furukawa, Yoshiaki

AU - Yokota, Takanori

AU - Wada, Keiji

AU - Taylor, J. Paul

AU - Pearson, Christopher E.

AU - Charlet-Berguerand, Nicolas

AU - Mizusawa, Hidehiro

AU - Nagai, Yoshitaka

AU - Ishikawa, Kinya

PY - 2017/4/5

Y1 - 2017/4/5

N2 - Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.

AB - Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.

KW - ALS

KW - Drosophila melanogaster

KW - RAN translation

KW - RNA chaperone

KW - RNA foci

KW - SCA31

KW - TDP-43

KW - microsatellite repeat expansion diseases

KW - ribonucleoprotein

UR - http://www.scopus.com/inward/record.url?scp=85016041911&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2017.02.046

DO - 10.1016/j.neuron.2017.02.046

M3 - Article

C2 - 28343865

AN - SCOPUS:85016041911

SN - 0896-6273

VL - 94

SP - 108-124.e7

JO - Neuron

JF - Neuron

IS - 1

ER -

Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this