Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis
Authors: M Nassif
U Woehlbier
C Cortez
M J M Bertrand
J M Matamala
C A Bergmann
S Beltran
C Hetz
D B Medinas
E Vicencio
S Matus
S Espinoza
B I Cortes
J Arcos
L Labrador
D Rojas-Rivera
M F Hernandez
P A Manque
L Bargsted
Journal: Molecular neurodegeneration (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: ALS; Autophagy; Beclin1; C13orf18, KIAA0226-like; Pacer
Affiliations: Center for Integrative Biology, Faculty of Science, Universidad Mayor, Camino la Piramide 5750, P.O.BOX 70086, Santiago, Chile., Center for Genomics and Bioinformatics, Faculty of Science, Universidad Mayor, Camino la Piramide, 5750, Santiago, Chile., Department of Neurological Sciences, Faculty of Medicine, University of Chile, Santiago, Chile., Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Independencia, 1027, Santiago, Chile., Fundación Ciencia & Vida, Zañartu 1482, 7780272, Santiago, Chile., Neurounion Biomedical Foundation, 7780272, Santiago, Chile., Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile., VIB Center for Inflammation Research, Technologiepark 927, Zwijnaarde, 9052, Ghent, Belgium., Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde, 9052, Ghent, Belgium., Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Independencia, 1027, Santiago, Chile., Buck Institute for Research on Aging, Novato, CA, 94945, USA., Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, 02115, USA., Center for Integrative Biology, Faculty of Science, Universidad Mayor, Camino la Piramide 5750, P.O.BOX 70086, Santiago, Chile. ., Center for Genomics and Bioinformatics, Faculty of Science, Universidad Mayor, Camino la Piramide, 5750, Santiago, Chile. ., Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA, 23298, USA. .

Abstract:  Background: Amyotrophic 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. Methods: Initially, 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 (SOD1G93A and TDP43A315T) 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. Results: Using 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 the induction of cell death. Conclusions: This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology. 

Retracted: No

PubPeer comments:
 Brought to my attention by a reader. * Red boxes: The HCT116 GAPDH panel in Figure 4B looks similar to two lanes in the HT29 GAPDH panel of Figure 5B. ![file] , 
 2021 retraction. https: www.nature.com articles s41598-021-82870-5 Retraction of: Scientific Reports https: doi.org 10.1038 srep04694 , published online 15 April 2014 The Editors have retracted this Article. Concerns were raised regarding a number of figures, specifically: - Figure 1B: the HCT116 p53+ + GAPDH band appears to be identical to the HT29 GADPH band for Figure 4A - Figure 1B: the hCT116 p53u2212 u2212 GADPH band appears to be identical to the HCT116 p53+ + GADPH band for Figure 4A - Figure 4A: the HCT116 p53+ + p-JNK band appears to be identical to the band for RKO JNK - Figure 4B: the HCT116p53u2212 u2212 control 5-FU(20mu) GAPDH band appears to be identical to the HT29 GAPDH band in Figure 5B The data reported in this Article are therefore unreliable. The Authors disagree with the retraction. ,