A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice.

Luis C Fernández-Beltrán,Debbie Williams,Juan Miguel Godoy-Corchuelo,Maria Losa-Fontangordo,Silvia Corrochano,Jorge Matias-Guiu

doi:10.3390/ijms22179553

Abstract

Amyotrophic lateral sclerosis (ALS) is a multifactorial and complex fatal degenerative disorder. A number of pathological mechanisms that lead to motor neuron death have been identified, although there are many unknowns in the disease aetiology of ALS. Alterations in lipid metabolism are well documented in the progression of ALS, both at the systemic level and in the spinal cord of mouse models and ALS patients. The origin of these lipid alterations remains unclear. This study aims to identify early lipid metabolic pathways altered before systemic metabolic symptoms in the spinal cord of mouse models of ALS. To do this, we performed a transcriptomic analysis of the spinal cord of SOD1G93A mice at an early disease stage, followed by a robust transcriptomic meta-analysis using publicly available RNA-seq data from the spinal cord of SOD1 mice at early and late symptomatic disease stages. The meta-analyses identified few lipid metabolic pathways dysregulated early that were exacerbated at symptomatic stages; mainly cholesterol biosynthesis, ceramide catabolism, and eicosanoid synthesis pathways. We present an insight into the pathological mechanisms in ALS, confirming that lipid metabolic alterations are transcriptionally dysregulated and are central to ALS aetiology, opening new options for the treatment of these devastating conditions.

Highlights

Accepted: 30 August 2021Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting primarily the degeneration of upper and lower motor neurons leading to muscle atrophy, paralysis, and death [1]
Mice, we performed RNA-sequencing analysis of female SOD1G93A and wild type littermate mice (n = 5) at early symptomatic disease stage (90 days of age, P90), which was before the onset of body weight loss
We found a total of 1173 genes differentially expressed in the spinal cord of SOD1G93A mice compared to wild type controls, with log2-fold change values between −1.5 and +1.5 (Figure 1A, and Supplementary Materials, Table S1)

Summary

Introduction

Accepted: 30 August 2021Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting primarily the degeneration of upper and lower motor neurons leading to muscle atrophy, paralysis, and death [1]. The great majority of cases are sporadic (around 90–95%) with the remaining 5–10% familial in nature (fALS) caused by different mutations. 1 (SOD1) gene (15–30% of fALS and up to 2% of the total of ALS cases) [2,3], these numbers might be underestimated due to the current limitations of genetic testing in sporadic cases. There are over 30 genes identified that are causative or modifiers of ALS. These genes have been crucial for understanding the aetiology of disease, providing evidence of the complexity and multifactorial nature of this complex disorder [4].

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