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
N1 - Funding Information:
We thank Hisae Kikuchi and Drs. Takeshi Kasama, Michi Okita, and Helena Akiko Popiel for their advice and technical support. We thank Drs. Francisco E. Baralle and Emanuele Buratti for the kind gifts of the TDP-43 bacterial expression constructs and for the proteins. We also thank Dr. Leonard Petrucelli for critical reading of the manuscript and helpful discussions. This work was supported in part by a grant from Core Research for Evolutional Science and Technology (H.M.) from the Japan Science and Technology Agency; by a Grant-in-Aid for Scientific Research on Innovative Areas (Synapse and Neurocircuit Pathology) (25110741, Y.N.) and the Strategic Research Program for Brain Sciences (Integrated Research on Neuropsychiatric Disorders) (11013026, Y.N.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by Grants-in-Aid for Scientific Research (A) (21249054, H.M. and K.I.) and for Scientific Research (C) (21591072 and 24591252, K.I.), and for Challenging Exploratory Research (24659438, Y.N.; 15K15334, T.I.) from the Japan Society for the Promotion of Science; by Health and Labour Sciences Research Grants for Research on Development of New Drugs (Y.N.) and for the Research Committee for Ataxic Diseases (H.M. and Y.N.) from the Ministry of Health, Labour and Welfare; and finally by a grant for Practical Research Projects for Rare/Intractable Diseases (16ek0109018h0003, Y.N) from the Japan Agency for Medical Research and Development.
Publisher Copyright:
© 2017 Elsevier Inc.
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
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U2 - 10.1016/j.neuron.2017.02.046
DO - 10.1016/j.neuron.2017.02.046
M3 - Article
C2 - 28343865
AN - SCOPUS:85016041911
VL - 94
SP - 108-124.e7
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 1
ER -