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

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.

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Among these metabolic defects, dysregulation of lipid homeostasis appeared as an early phenomenon [ 6 ]. These results align with growing evidence demonstrating that lipid metabolism dysfunction is not just a consequence of disease progression but rather plays a causal role [ 22 , 23 , 24 ]. Dysfunctions of the lipid metabolism are observed in the central nervous system, blood, and muscles of ALS patients and different mouse models, often long before the appearance of motor symptoms [ 25 ].…”

Apolipoprotein A1 Enhances Endothelial Cell Survival in anIn VitroModel of ALS

“…In support of this possibility, hyperlipidemia, especially high plasma levels of total cholesterol or LDL/HDL ratio, was associated with an increase in ALS patient survival of >12 months ( Dupuis et al, 2008 ). In addition, a recently reported transcriptomic meta-analysis of the spinal cords from G93A SOD1 mice confirmed lipid metabolism dysregulation as an early pathologic disease mechanism ( Fernández-Beltrán et al, 2021 ), supporting previous observations in a mouse model of ALS and ALS patients ( Chaves-Filho et al, 2019 ; González De Aguilar, 2019 ).…”

Singling out motor neurons in the age of single-cell transcriptomics

“…Yet each of these techniques has substantial limitations if the goal is to discover the full breadth of transcriptional diversity. Bulk transcriptomic studies have succeeded in defining the broad categories of changes in gene expression associated with diseases of the spinal cord [27,28], but this technique involves averaging over cellular heterogeneity [14]. In contrast, studying the gene expression profiles of individual cells enables refined characterization of neuronal diversity, as well as their individuated responses to disease-associated perturbations.…”