ALS-linked protein disulfide isomerase variants cause motor dysfunction

Ute Woehlbier, Alicia Colombo, Mirva J. Saaranen, Viviana Pérez, Jorge Ojeda, Fernando J. Bustos, Catherine I. Andreu, Mauricio Torres, Vicente Valenzuela, Danilo B. Medinas, Pablo Rozas, Rene L. Vidal, Rodrigo Lopez-Gonzalez, Johnny Salameh, Sara Fernandez-Collemann, Natalia Muñoz, Soledad Matus, Ricardo Armisen, Alfredo Sagredo, Karina PalmaThergiory Irrazabal, Sandra Almeida, Paloma Gonzalez-Perez, Mario Campero, Fen Biao Gao, Pablo Henny, Brigitte Van Zundert, Lloyd W. Ruddock, Miguel L. Concha, Juan P. Henriquez, Robert H. Brown, Claudio Hetz

Resultado de la investigación: Article

42 Citas (Scopus)

Resumen

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.

Idioma originalEnglish
Páginas (desde-hasta)845-865
Número de páginas21
PublicaciónEMBO Journal
Volumen35
N.º8
DOI
EstadoPublished - 15 abr 2016

Huella dactilar

Protein Disulfide-Isomerases
Amyotrophic Lateral Sclerosis
Endoplasmic Reticulum
Motor Neurons
Defects
Neurology
Biomarkers
Zebrafish
Mutant Proteins
Cell culture
Synapses
Nervous System
Virulence
Screening
Cell Culture Techniques
Genes
Mutation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Citar esto

Woehlbier, U., Colombo, A., Saaranen, M. J., Pérez, V., Ojeda, J., Bustos, F. J., ... Hetz, C. (2016). ALS-linked protein disulfide isomerase variants cause motor dysfunction. EMBO Journal, 35(8), 845-865. https://doi.org/10.15252/embj.201592224
Woehlbier, Ute ; Colombo, Alicia ; Saaranen, Mirva J. ; Pérez, Viviana ; Ojeda, Jorge ; Bustos, Fernando J. ; Andreu, Catherine I. ; Torres, Mauricio ; Valenzuela, Vicente ; Medinas, Danilo B. ; Rozas, Pablo ; Vidal, Rene L. ; Lopez-Gonzalez, Rodrigo ; Salameh, Johnny ; Fernandez-Collemann, Sara ; Muñoz, Natalia ; Matus, Soledad ; Armisen, Ricardo ; Sagredo, Alfredo ; Palma, Karina ; Irrazabal, Thergiory ; Almeida, Sandra ; Gonzalez-Perez, Paloma ; Campero, Mario ; Gao, Fen Biao ; Henny, Pablo ; Van Zundert, Brigitte ; Ruddock, Lloyd W. ; Concha, Miguel L. ; Henriquez, Juan P. ; Brown, Robert H. ; Hetz, Claudio. / ALS-linked protein disulfide isomerase variants cause motor dysfunction. En: EMBO Journal. 2016 ; Vol. 35, N.º 8. pp. 845-865.
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title = "ALS-linked protein disulfide isomerase variants cause motor dysfunction",
abstract = "Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.",
keywords = "amyotrophic lateral sclerosis, ERp57, PDIA1, protein disulfide isomerase",
author = "Ute Woehlbier and Alicia Colombo and Saaranen, {Mirva J.} and Viviana P{\'e}rez and Jorge Ojeda and Bustos, {Fernando J.} and Andreu, {Catherine I.} and Mauricio Torres and Vicente Valenzuela and Medinas, {Danilo B.} and Pablo Rozas and Vidal, {Rene L.} and Rodrigo Lopez-Gonzalez and Johnny Salameh and Sara Fernandez-Collemann and Natalia Mu{\~n}oz and Soledad Matus and Ricardo Armisen and Alfredo Sagredo and Karina Palma and Thergiory Irrazabal and Sandra Almeida and Paloma Gonzalez-Perez and Mario Campero and Gao, {Fen Biao} and Pablo Henny and {Van Zundert}, Brigitte and Ruddock, {Lloyd W.} and Concha, {Miguel L.} and Henriquez, {Juan P.} and Brown, {Robert H.} and Claudio Hetz",
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Woehlbier, U, Colombo, A, Saaranen, MJ, Pérez, V, Ojeda, J, Bustos, FJ, Andreu, CI, Torres, M, Valenzuela, V, Medinas, DB, Rozas, P, Vidal, RL, Lopez-Gonzalez, R, Salameh, J, Fernandez-Collemann, S, Muñoz, N, Matus, S, Armisen, R, Sagredo, A, Palma, K, Irrazabal, T, Almeida, S, Gonzalez-Perez, P, Campero, M, Gao, FB, Henny, P, Van Zundert, B, Ruddock, LW, Concha, ML, Henriquez, JP, Brown, RH & Hetz, C 2016, 'ALS-linked protein disulfide isomerase variants cause motor dysfunction', EMBO Journal, vol. 35, n.º 8, pp. 845-865. https://doi.org/10.15252/embj.201592224

ALS-linked protein disulfide isomerase variants cause motor dysfunction. / Woehlbier, Ute; Colombo, Alicia; Saaranen, Mirva J.; Pérez, Viviana; Ojeda, Jorge; Bustos, Fernando J.; Andreu, Catherine I.; Torres, Mauricio; Valenzuela, Vicente; Medinas, Danilo B.; Rozas, Pablo; Vidal, Rene L.; Lopez-Gonzalez, Rodrigo; Salameh, Johnny; Fernandez-Collemann, Sara; Muñoz, Natalia; Matus, Soledad; Armisen, Ricardo; Sagredo, Alfredo; Palma, Karina; Irrazabal, Thergiory; Almeida, Sandra; Gonzalez-Perez, Paloma; Campero, Mario; Gao, Fen Biao; Henny, Pablo; Van Zundert, Brigitte; Ruddock, Lloyd W.; Concha, Miguel L.; Henriquez, Juan P.; Brown, Robert H.; Hetz, Claudio.

En: EMBO Journal, Vol. 35, N.º 8, 15.04.2016, p. 845-865.

Resultado de la investigación: Article

TY - JOUR

T1 - ALS-linked protein disulfide isomerase variants cause motor dysfunction

AU - Woehlbier, Ute

AU - Colombo, Alicia

AU - Saaranen, Mirva J.

AU - Pérez, Viviana

AU - Ojeda, Jorge

AU - Bustos, Fernando J.

AU - Andreu, Catherine I.

AU - Torres, Mauricio

AU - Valenzuela, Vicente

AU - Medinas, Danilo B.

AU - Rozas, Pablo

AU - Vidal, Rene L.

AU - Lopez-Gonzalez, Rodrigo

AU - Salameh, Johnny

AU - Fernandez-Collemann, Sara

AU - Muñoz, Natalia

AU - Matus, Soledad

AU - Armisen, Ricardo

AU - Sagredo, Alfredo

AU - Palma, Karina

AU - Irrazabal, Thergiory

AU - Almeida, Sandra

AU - Gonzalez-Perez, Paloma

AU - Campero, Mario

AU - Gao, Fen Biao

AU - Henny, Pablo

AU - Van Zundert, Brigitte

AU - Ruddock, Lloyd W.

AU - Concha, Miguel L.

AU - Henriquez, Juan P.

AU - Brown, Robert H.

AU - Hetz, Claudio

PY - 2016/4/15

Y1 - 2016/4/15

N2 - Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.

AB - Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) are ER foldases identified as possible ALS biomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized four ALS-linked mutations recently identified in two major PDI genes, PDIA1 and PDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of these PDI variants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutant PDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of these PDI mutants. Finally, targeting ERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifies ER proteostasis imbalance as a risk factor for ALS, driving initial stages of the disease.

KW - amyotrophic lateral sclerosis

KW - ERp57

KW - PDIA1

KW - protein disulfide isomerase

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U2 - 10.15252/embj.201592224

DO - 10.15252/embj.201592224

M3 - Article

C2 - 26869642

AN - SCOPUS:84958594182

VL - 35

SP - 845

EP - 865

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 8

ER -

Woehlbier U, Colombo A, Saaranen MJ, Pérez V, Ojeda J, Bustos FJ y otros. ALS-linked protein disulfide isomerase variants cause motor dysfunction. EMBO Journal. 2016 abr 15;35(8):845-865. https://doi.org/10.15252/embj.201592224