Collagen XIX Alpha 1 Improves Prognosis in Amyotrophic Lateral Sclerosis.

Alberto García Redondo,Pilar Cordero Vázquez,Christian Lunetta,Rosario Osta,Pilar Zaragoza,Juan F Roy,Laura Moreno,Lucía Galán,Miguel A Martín,Marina Mora,Claudia Tarlarini,Jesús Mora,Silvana Penco,Gabriela Atencia Cibreiro,Ana C Calvo,Elena Pegoraro,Alexandra Juárez Rufián,Paz Torre Merino,Jesús Esteban,Juan Manuel Corral Cano ,Marı́a Jesús Muñoz ,Adrián Galiana ,P Larrodé ,José Luís Muñoz-Blanco ,Gian Domenico Sorarù

doi:10.14336/ad.2018.0917

Abstract

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.

Highlights

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron loss and muscle weakness
The findings in this study revealed that COL19A1 levels in muscle biopsies and blood samples from ALS patients can be considered a prognostic biomarker to accurately monitor the disease progression, especially in those patients that share a high disability in the first symptomatic stages of the disease
COL19A1 gene and protein levels were significantly associated with the ALS patient group with respect to healthy controls and patients with other neuropathies (ONP), suggesting that COL19A1 levels can be useful as molecular support for diagnosis in this tissue

Summary

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron loss and muscle weakness. Dementia is relatively frequent in ALS and may be a consequence of either frontotemporal lobar degeneration (FTLD) or a result of co-existing Alzheimer disease [6,7] In this complex scenario and in spite of the numerous studies attempting to find specific gene/protein targets exclusive for ALS and characteristic of both familial and sporadic cases, the prognosis of the disease remains poor. Another main challenge relies on the fact that ALS is a multifactorial and relentlessly progressive disease, which hinders the use of an effective treatment. Previous studies by our research workgroup on transgenic SOD1G93A mice suggested five genes, Mef2c (myocyte enhancer factor 2C), Gsr (oxidative stress metabolism), Col19a1 (collagen, type XIX, alpha 1), Calm (calmodulin 1), and Snx (sorting nexin 10), as potential genetic biomarkers of longevity in transgenic

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Conclusion