Advanced search
1 file | 5.85 MB Add to list

Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis

Author
Organization
Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis.MethodsInitially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1(G93A) and TDP43(A315T)) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death.ResultsUsing an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with theinduction of cell death.ConclusionsThis study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology.
Keywords
AMYOTROPHIC-LATERAL-SCLEROSIS, MOTOR-NEURON DEGENERATION, SOD1(G93A), MOUSE MODEL, COPY-NUMBER VARIATION, HEXANUCLEOTIDE REPEAT, CERVICAL-CANCER, DISTINCT ROLES, WILD-TYPE, RUBICON, MUTATIONS, ALS, Autophagy, Beclin1, C13orf18, KIAA0226-like, Pacer, Rubicon, Rubicon-like, SOD1, TDP43

Downloads

  • 4155 19Beltran.pdf
    • full text (Published version)
    • |
    • open access
    • |
    • PDF
    • |
    • 5.85 MB

Citation

Please use this url to cite or link to this publication:

MLA
Beltran, S., et al. “Network Approach Identifies Pacer as an Autophagy Protein Involved in ALS Pathogenesis.” MOLECULAR NEURODEGENERATION, vol. 14, 2019, doi:10.1186/s13024-019-0313-9.
APA
Beltran, S., Nassif, M., Vicencio, E., Arcos, J., Labrador, L., Cortes, B. I., … Woehlbier, U. (2019). Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis. MOLECULAR NEURODEGENERATION, 14. https://doi.org/10.1186/s13024-019-0313-9
Chicago author-date
Beltran, S., M. Nassif, E. Vicencio, J. Arcos, L. Labrador, B. I. Cortes, C. Cortez, et al. 2019. “Network Approach Identifies Pacer as an Autophagy Protein Involved in ALS Pathogenesis.” MOLECULAR NEURODEGENERATION 14. https://doi.org/10.1186/s13024-019-0313-9.
Chicago author-date (all authors)
Beltran, S., M. Nassif, E. Vicencio, J. Arcos, L. Labrador, B. I. Cortes, C. Cortez, C. A. Bergmann, S. Espinoza, M. F. Hernandez, J. M. Matamala, L. Bargsted, S. Matus, Diego Rojas Rivera, Mathieu Bertrand, D. B. Medinas, C. Hetz, P. A. Manque, and U. Woehlbier. 2019. “Network Approach Identifies Pacer as an Autophagy Protein Involved in ALS Pathogenesis.” MOLECULAR NEURODEGENERATION 14. doi:10.1186/s13024-019-0313-9.
Vancouver
1.
Beltran S, Nassif M, Vicencio E, Arcos J, Labrador L, Cortes BI, et al. Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis. MOLECULAR NEURODEGENERATION. 2019;14.
IEEE
[1]
S. Beltran et al., “Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis,” MOLECULAR NEURODEGENERATION, vol. 14, 2019.
@article{8650576,
  abstract     = {{BackgroundAmyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis.MethodsInitially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1(G93A) and TDP43(A315T)) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death.ResultsUsing an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with theinduction of cell death.ConclusionsThis study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology.}},
  articleno    = {{14}},
  author       = {{Beltran, S. and Nassif, M. and Vicencio, E. and Arcos, J. and Labrador, L. and Cortes, B. I. and Cortez, C. and Bergmann, C. A. and Espinoza, S. and Hernandez, M. F. and Matamala, J. M. and Bargsted, L. and Matus, S. and Rojas Rivera, Diego and Bertrand, Mathieu and Medinas, D. B. and Hetz, C. and Manque, P. A. and Woehlbier, U.}},
  issn         = {{1750-1326}},
  journal      = {{MOLECULAR NEURODEGENERATION}},
  keywords     = {{AMYOTROPHIC-LATERAL-SCLEROSIS,MOTOR-NEURON DEGENERATION,SOD1(G93A),MOUSE MODEL,COPY-NUMBER VARIATION,HEXANUCLEOTIDE REPEAT,CERVICAL-CANCER,DISTINCT ROLES,WILD-TYPE,RUBICON,MUTATIONS,ALS,Autophagy,Beclin1,C13orf18,KIAA0226-like,Pacer,Rubicon,Rubicon-like,SOD1,TDP43}},
  language     = {{eng}},
  pages        = {{18}},
  title        = {{Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis}},
  url          = {{http://dx.doi.org/10.1186/s13024-019-0313-9}},
  volume       = {{14}},
  year         = {{2019}},
}

Altmetric
View in Altmetric
Web of Science
Times cited: