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Aging and disease    2019, Vol. 10 Issue (2) : 278-292     DOI: 10.14336/AD.2018.0917
Original Article |
Collagen XIX Alpha 1 Improves Prognosis in Amyotrophic Lateral Sclerosis
Ana C. Calvo1,*, Gabriela Atencia Cibreiro2, Paz Torre Merino2, Juan F. Roy3, Adrián Galiana4, Alexandra Juárez Rufián2, Juan M. Cano5, Miguel A. Martín6, Laura Moreno1, Pilar Larrodé1, Pilar Cordero Vázquez2, Lucía Galán7, Jesús Mora8, José L. Muñoz-Blanco9, María J. Muñoz1, Pilar Zaragoza1, Elena Pegoraro10, Gianni Sorarù10, Marina Mora11, Christian Lunetta12, Silvana Penco13, Claudia Tarlarini13, Jesús Esteban2, Rosario Osta1, Alberto García Redondo2
1LAGENBIO (Laboratory of Genetics and Biochemistry), Faculty of Veterinary-IIS, IA2-CITA, University of Zaragoza, Zaragoza, Spain.
2Neurology Department, ALS Unit, CIBERER U-723, Health Research Institute, October 12th Hospital “IIS I+12”, Madrid, Spain.
3Ferkauf Graduate School of Psychology, Yeshiva University, NY 10461, USA.
4Servicio de Reumatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
5Orthopaedic Surgery Department, October 12th Hospital, Madrid, Spain.
6Grupo Enfermedades Mitocondriales y Neuromusculares, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), U723-CIBERER, Madrid, España.
7Neurology Department, ALS Unit, Clínico Universitario San Carlos Hospital, Madrid, Spain.
8Neurology Department, ALS Unit, Carlos III Hospital, Madrid, Spain.
9Neurology Department, ALS Unit, Health Research Institute, Gregorio Marañón Hospital “IISGM”, Madrid, Spain.
10Neurological Clinic, Department of Neurosciences, University of Padova, Padova, Italy.
11Muscle Cell Biology Laboratory, Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
12NEMO (NEuroMuscular Omnicentre) Clinical Center, Fondazione Serena Onlus, Milan, Italy.
13Medical Genetics Unit, Department of Laboratory Medicine, Niguarda Ca’ Granda Hospital, Milan, Italy.
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The identification of more reliable diagnostic or prognostic biomarkers in age-related neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), is urgently needed. The objective in this study was to identify more reliable prognostic biomarkers of ALS mirroring neurodegeneration that could be of help in clinical trials. A total of 268 participants from three cohorts were included in this study. The muscle and blood cohorts were analyzed in two cross-sectional studies, while the serial blood cohort was analyzed in a longitudinal study at 6-monthly intervals. Fifteen target genes and fourteen proteins involved in muscle physiology and differentiation, metabolic processes and neuromuscular junction dismantlement were studied in the three cohorts. In the muscle biopsy cohort, the risk for a higher mortality in an ALS patient that showed high Collagen type XIX, alpha 1 (COL19A1) protein levels and a fast progression of the disease was 70.5% (P < 0.05), while in the blood cohort, this risk was 20% (P < 0.01). In the serial blood cohort, the linear mixed model analysis showed a significant association between increasing COL19A1 gene levels along disease progression and a faster progression during the follow-up period of 24 months (P < 0.05). Additionally, higher COL19A1 levels and a faster progression increased 17.9% the mortality risk (P < 0.01). We provide new evidence that COL19A1 can be considered a prognostic biomarker that could help the selection of homogeneous groups of patients for upcoming clinical trial and may be pointed out as a promising therapeutic target in ALS.

Keywords Collagen XIX type A1      ALS      prognostic biomarker      neurodegeneration      disease progression     
Corresponding Authors: Calvo Ana C.   
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These authors contributed equally to this work.

Just Accepted Date: 11 December 2018   Issue Date: 05 April 2019
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Articles by authors
Ana C. Calvo
Gabriela Atencia Cibreiro
Paz Torre Merino
Juan F. Roy
Adrián Galiana
Alexandra Juárez Rufián
Juan M. Cano
Miguel A. Martín
Laura Moreno
Pilar Larrodé
Pilar Cordero Vázquez
Lucía Galán
Jesús Mora
José L. Muñoz-Blanco
María J. Muñoz
Pilar Zaragoza
Elena Pegoraro
Gianni Sorarù
Marina Mora
Christian Lunetta
Silvana Penco
Claudia Tarlarini
Jesús Esteban
Rosario Osta
Alberto García Redondo
Cite this article:   
Ana C. Calvo,Gabriela Atencia Cibreiro,Paz Torre Merino, et al. Collagen XIX Alpha 1 Improves Prognosis in Amyotrophic Lateral Sclerosis[J]. Aging and disease, 2019, 10(2): 278-292.
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Type of cohort (N)Muscle biopsy cohort* (N = 87)
ALS patientsONP patientsHealthy controls
Patients' characteristics(n =49)(n = 14)(n = 24)
Gender (n)Female15819
Age at illness onset (mean ± SD)57.02 ± 12.4243.79 ± 16.02
Age at biopsy (mean ± SD)58.65 ± 12.5242.34 ± 25.8955.07 ± 26.07
Disease duration, months (mean ± SD)19.54 ± 25.15
Clinical Phenotype (n)ALS, spinal42
ALS, bulbar6
AD (Early)1
ALSFRS-r at biopsy (mean ± SD)40.24 ± 6.20
El Escorial criteria at onset (n)Unavailable33
Genetic Diagnosis (n)SALS26
Table 1  General and clinical characteristics of the study subjects in the muscle biopsy study cohort.
Type of cohort (N)Blood cohort* (N = 141)
ALS patientsONP patientsHealthy controls
Patients’ characteristics(n = 59)(n= 24)(n = 58)
Gender (n)Female251031
Age at illness onset (mean ± SD)60.98 ± 14.0743.79 ± 16.02
Age at biopsy (mean ± SD)62.10 ± 14.0055.74 ± 12.3255.74 ± 12.31
Disease duration, months (mean ± SD)14.53 ± 14.66
Clinical Phenotype (n)ALS59
AD (Early)1
HPP (Type-1)1
MD (Type-1)9
MD (Type-2)1
Site at onset (n)Lower limb27
Upper limb17
ALSFRS-r at onset (mean ± SD)42.71 ± 6.86
ALSFRS-r at biopsy (mean ± SD)34.47 ± 7.82
El Escorial criteria at onset (n)Unavailable18
Genetic Diagnosis (n)SALS33
FALS (4m**)18
Table 2  General and clinical characteristics of the study subjects in the blood study cohort.
Figure 1.  Flow diagram of the three study cohorts and overview of the study design. A total of 148 ALS patients were enrolled in two cross-sectional studies and one longitudinal study to detect associations among molecular markers and clinical variables in skeletal muscle biopsy (ALS muscle biopsy cohort) and blood samples (ALS blood cohort) and to identify prognostic biomarkers along the disease progression, especially in serial blood samples.
Type of cohort (N)Serial blood cohort * (N = 40)
ALS patients (n =40)
Patients' characteristicsOnset6 months12 months18 months24 months
Gender (n)Female15
Age at illness onset (mean ± SD)57.02 ± 12.42
Disease duration, months (mean ± SD)57.53 ± 23.48
Clinical Phenotype (n)SALS, UMN and LMN spinal25
SALS, UMN spinal1
SALS, LMN spinal14
ALSFRS-r (mean ± SD)27.8 ± 5.4723.8 ± 5.9419.6 ± 6.2718.5 ± 6.7617.6 ± 6.76
El Escorial criteria at onset (n)Defined25
Forced vital capacity (FVC) (%)10.4 ± 6.1114.6 ± 6.9915.0 ± 10.4417.8 ± 11.1220.6 ± 15.74
Body mass index (BMI) (Kg/m2)26.5 ± 3.8126.3 ± 3.8225.9 ± 4.1126.0 ± 3.7125.3 ± 3.55
Genetic Diagnosis (n)SALS40
Table 3  General and clinical characteristics of sporadic ALS patients in the serial blood study cohort.
Gene nameGene SymbolAssay ID
Ankyrin repeat domain 1 (cardiac muscle)ANKRD1Hs00173317_m1
Collagen, type XIX, alpha 1COL19A1Hs00156940_m1
F-box protein 32FBXO32Hs01041408_m1
Glycogen synthase kinase 3GSK3Hs01047719_m1
Glutathione reductaseGSRHs00167317_m1
Inositol(myo)-1(or 4)-monophosphatase 1IMPA1Hs04188597_m1
Myocyte enhancer factor 2CMEF2CHs00231149_m1
Myogenin (myogenic factor 4)MYOGHs01072232_m1
Reticulon 4RTN4 (NOGO A)Hs00199671_m1
Ras-related associated with diabetesRRADHs00188163_m1
Sorting nexin 10SNX10Hs00203362_m1
Superoxide dismutase 1, solubleSOD1Hs00533490_m1
Vacuolar protein sorting 54 homolog (S. cerevisiae )VPS54Hs00212957_m1
Table 4  Taqman® probe and primer mixtures used in gene expression assays.
Protein nameProtein SymbolReference number, primary antibodies
Anti-Apoptosis-inducing factor, mitochondrion-associated, 1AIFM1SAB2100079, anti-rabbit, Sigma-Aldrich
Ankyrin repeat domain 1 (cardiac muscle)ANKRD1SAB1101413, anti-rabbit antibody, Sigma-Aldrich
Aspartate transcarbamylaseCADSAB2100334, anti-rabbit, Sigma-Aldrich
Collagen, type XIX, alpha 1COL19A1H00001310-A01, anti-mouse, Novus Biologicals
Coenzyme Q3 homologCoQ3WH0051805M1, anti-mouse, Sigma-Aldrich
F-box protein 32FBXO32ab67866, anti-mouse, ABCAM
Glutathione reductaseGSRWH0002936M1, anti-mouse, Sigma-Aldrich
Inositol(myo)-1(or 4)-monophosphatase 1IMPA1SAB2103588, anti-rabbit, Sigma-Aldrich
Myogenin (myogenic factor 4)MYOGWH0004656M1, anti-mouse, Sigma-Aldrich
Anti-CoQ1PDSS1AV46195, anti-rabbit, Sigma-Aldrich
Reticulon 4RTN4 (NOGO A)R3282, anti-rabbit, Sigma-Aldrich
SarcolipinSLNab25860, anti-rabbit, ABCAMK
Sorting nexin 10SNX10WH0029887M1, anti-mouse, Sigma-Aldrich
Vacuolar protein sorting 54 homolog (S. cerevisiae)VPS54SAB1401701, anti-mouse, Sigma-Aldrich
Table 5  Primary antibodies used in protein expression assays.
Figure 2.  Relative gene and protein expression levels of COL19A1 in the muscle biopsy study cohort. Gene and protein expression levels of COL19A1 in healthy subjects, ALS patients and other neuropathies patients (A). Kruskal Wallis tests showed significant differences among ALS patients and the other two groups under study, when gene and protein expression levels were tested (P < 0.001, **). (B) Areas under ROC curves (AUC) of gene and protein expression of COL19A1 were calculated to test its support for diagnosis criterion in ALS patients (P <0.001, **). A total of 49 ALS (FALS and SALS) participants were included in this study and matched with 24 control individuals, and 14 ONP; SE: standard error.
Figure 3.  Relative gene expression analysis in the blood study cohort. Transcriptional expression levels of MEF2C , NOGO A , SOD1 , COL19A1 and SNX10 in healthy subjects, ALS patients and other neuropathies patients. (A) Kruskal Wallis tests showed significant differences among ALS patients and healthy participants in all the cases except for SNX10 . Significant differences among other neuropathies patient group and ALS patient group were found in all the cases except for NOGO A and SOD1 . (B) Area under ROC curves of COL19A1 and the ratios COL19A1 /NOGO A and SOD1 /NOGO A were calculated in the sporadic ALS patient group. Significant differences were found between COL19A1 and the ratio COL19A1 /NOGO A , and between COL19A1 and the ratio SOD1 /NOGO A . A total of 141 participants were included in this study: 58 control individuals, 24 other neuropathology’s individuals and 59 ALS patients (FALS and SALS patients); (*P < 0.05; ** P < 0.001), SE: standard error.
Figure 4.  Linear mixed model analysis in the serial blood study cohort. (A) Linear mixed model analysis showed a significant relationship among a faster disease progression and high COL19A1 levels from symptom onset, each dashed line corresponds to the COL19A1 levels from each patient. (B) Mean change from baseline in the ALSFRS-r score in patients that were monitored at 6-monthly intervals during a follow-up period of 24 months from the symptom onset that show COL19A1 levels above (green dot and line) and below (blue dot and line) average at first evaluation. Student's-t test was performed to analyze statistical differences between groups (P < 0.001). A total of 40 SALS patients from the serial blood study cohort were included.
Group of ALS patientsNCOL19A1 levelsALSFRS-r slopeEstimateHR (95% CI)P value
Muscle cohort*49above the mean average (1.06)≥ 1 points/month0.2031.225 (1.058 - 1.418)0.007
Blood cohort59above the mean average (0.819)≥ 1 points/month0.7482.114 (1.134 - 3.941)0.019
Serial blood cohort40above the mean average (0.819)≥ 1 points/month0.1641.179 (1.046 - 1.327)0.007
Table 6  Prognostic nature of COL19A1 levels in the three cohorts under study.
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