CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration

Ashleigh E. Schaffer; Veerle R. C. Eggens; Ahmet Okay Caglayan; Miriam S. Reuter; Eric Scott; Nicole G. Coufal; Jennifer L. Silhavy; Yuanchao Xue; Hulya Kayserili; Katsuhito Yasuno; Rasim Ozgur Rosti; Mostafa Abdellateef; Caner Caglar; Paul R. Kasher; J. Leonie Cazemier; Marian A. Weterman; Vincent Cantagrel; Na Cai; Christiane Zweier; Umut Altunoglu; N. Bilge Satkin; Fesih Aktar; Beyhan Tuysuz; Cengiz Yalcinkaya; Huseyin Caksen; Kaya Bilguvar; Xiang-Dong Fu; Christopher R. Trotta; Stacey Gabriel; André Reis; Murat Gunel; Frank Baas; Joseph G. Gleeson

doi:https://doi.org/10.1016/j.cell.2014.03.049

CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration

Ashleigh E. Schaffer, Veerle R. C. Eggens, Ahmet Okay Caglayan, Miriam S. Reuter, Eric Scott, Nicole G. Coufal, Jennifer L. Silhavy, Yuanchao Xue, Hulya Kayserili, Katsuhito Yasuno, Rasim Ozgur Rosti, Mostafa Abdellateef, Caner Caglar, Paul R. Kasher, J. Leonie Cazemier, Marian A. Weterman, Vincent Cantagrel, Na Cai, Christiane Zweier, Umut AltunogluN. Bilge Satkin, Fesih Aktar, Beyhan Tuysuz, Cengiz Yalcinkaya, Huseyin Caksen, Kaya Bilguvar, Xiang-Dong Fu, Christopher R. Trotta, Stacey Gabriel, André Reis, Murat Gunel, Frank Baas, Joseph G. Gleeson

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

193 Citations (Scopus)

Abstract

Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans

Original language	English
Pages (from-to)	651-663
Journal	Cell
Volume	157
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2014.03.049
Publication status	Published - 2014

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https://doi.org/10.1016/j.cell.2014.03.049

Cite this

Schaffer, A. E., Eggens, V. R. C., Caglayan, A. O., Reuter, M. S., Scott, E., Coufal, N. G., Silhavy, J. L., Xue, Y., Kayserili, H., Yasuno, K., Rosti, R. O., Abdellateef, M., Caglar, C., Kasher, P. R., Cazemier, J. L., Weterman, M. A., Cantagrel, V., Cai, N., Zweier, C., ... Gleeson, J. G. (2014). CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell, 157(3), 651-663. https://doi.org/10.1016/j.cell.2014.03.049

@article{e8f20e8c8bba450ca139703d9dd82f8c,

title = "CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration",

abstract = "Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans",

author = "Schaffer, {Ashleigh E.} and Eggens, {Veerle R. C.} and Caglayan, {Ahmet Okay} and Reuter, {Miriam S.} and Eric Scott and Coufal, {Nicole G.} and Silhavy, {Jennifer L.} and Yuanchao Xue and Hulya Kayserili and Katsuhito Yasuno and Rosti, {Rasim Ozgur} and Mostafa Abdellateef and Caner Caglar and Kasher, {Paul R.} and Cazemier, {J. Leonie} and Weterman, {Marian A.} and Vincent Cantagrel and Na Cai and Christiane Zweier and Umut Altunoglu and Satkin, {N. Bilge} and Fesih Aktar and Beyhan Tuysuz and Cengiz Yalcinkaya and Huseyin Caksen and Kaya Bilguvar and Xiang-Dong Fu and Trotta, {Christopher R.} and Stacey Gabriel and Andr{\'e} Reis and Murat Gunel and Frank Baas and Gleeson, {Joseph G.}",

year = "2014",

doi = "https://doi.org/10.1016/j.cell.2014.03.049",

language = "English",

volume = "157",

pages = "651--663",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

Schaffer, AE, Eggens, VRC, Caglayan, AO, Reuter, MS, Scott, E, Coufal, NG, Silhavy, JL, Xue, Y, Kayserili, H, Yasuno, K, Rosti, RO, Abdellateef, M, Caglar, C, Kasher, PR, Cazemier, JL, Weterman, MA, Cantagrel, V, Cai, N, Zweier, C, Altunoglu, U, Satkin, NB, Aktar, F, Tuysuz, B, Yalcinkaya, C, Caksen, H, Bilguvar, K, Fu, X-D, Trotta, CR, Gabriel, S, Reis, A, Gunel, M, Baas, F & Gleeson, JG 2014, 'CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration', Cell, vol. 157, no. 3, pp. 651-663. https://doi.org/10.1016/j.cell.2014.03.049

TY - JOUR

T1 - CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration

AU - Schaffer, Ashleigh E.

AU - Eggens, Veerle R. C.

AU - Caglayan, Ahmet Okay

AU - Reuter, Miriam S.

AU - Scott, Eric

AU - Coufal, Nicole G.

AU - Silhavy, Jennifer L.

AU - Xue, Yuanchao

AU - Kayserili, Hulya

AU - Yasuno, Katsuhito

AU - Rosti, Rasim Ozgur

AU - Abdellateef, Mostafa

AU - Caglar, Caner

AU - Kasher, Paul R.

AU - Cazemier, J. Leonie

AU - Weterman, Marian A.

AU - Cantagrel, Vincent

AU - Cai, Na

AU - Zweier, Christiane

AU - Altunoglu, Umut

AU - Satkin, N. Bilge

AU - Aktar, Fesih

AU - Tuysuz, Beyhan

AU - Yalcinkaya, Cengiz

AU - Caksen, Huseyin

AU - Bilguvar, Kaya

AU - Fu, Xiang-Dong

AU - Trotta, Christopher R.

AU - Gabriel, Stacey

AU - Reis, André

AU - Gunel, Murat

AU - Baas, Frank

AU - Gleeson, Joseph G.

PY - 2014

Y1 - 2014

N2 - Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans

AB - Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans

U2 - https://doi.org/10.1016/j.cell.2014.03.049

DO - https://doi.org/10.1016/j.cell.2014.03.049

M3 - Article

C2 - 24766810

SN - 0092-8674

VL - 157

SP - 651

EP - 663

JO - Cell

JF - Cell

IS - 3

ER -