Can Transcriptomics Cut the Gordian Knot of Amyotrophic Lateral Sclerosis?

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disease characterized by the loss of upper and lower motor neurons, progressive muscle atrophy, paralysis and death, which occurs within 2-5 years of diagnosis. Most cases appear sporadically but some are familial, usually inherited in an autosomal dominant pattern. It is postulated that the disease results from the combination of multiple pathogenic mechanisms, which affect not only motor neurons but also non-neuronal neighboring cells. Together with the understanding of this intriguing cell biology, important challenges in the field concern the design of effective curative treatments and the discovery of molecular biomarkers for early diagnosis and accurate monitoring of disease progression. During the last decade, transcriptomics has represented a promising approach to address these questions. In this review, we revisit the major findings of the numerous studies that analyzed global gene expression in tissues and cells from biopsy or post-mortem specimens of ALS patients and related animal models. These studies corroborated the implication of previously described disease pathways, and investigated the role of new genes in the pathological process. In addition, they also identified gene expression changes that could be used as candidate biomarkers for the diagnosis and follow-up of ALS. The limitations of these transcriptomics approaches will be also discussed.

Mitochondrial Oxidative Phosphorylation Transcriptome Alterations in Human Amyotrophic Lateral Sclerosis Spinal Cord and Blood

“…In ALS research, while there have been several transcriptomic studies of central nervous and peripheral human tissues, animal and cell models, the complete picture is still being elucidated. Large lists of differentially expressed genes have been generated (Dangond et al 2004;Jiang et al 2005;Malaspina and de Belleroche 2004;Malaspina et al 2001;Rabin et al 2010;Saris et al 2009;Wang et al 2006;Zhang et al 2011), and although there are discrepancies between individual members of gene lists, there is a high degree of overlap in the molecular pathways predicted to be involved in this complex disease (Henriques and Gonzalez De Aguilar 2011;Heath et al 2013).…”

Integrated Analysis of Transcriptomic and Proteomic Data

“…Overall comparison of existing technologies and most recent RNA-Seq technology can be found in recent reviews by Nicole Roy et al [31] and Schirmer et al [32]. Use of different transcriptomic technologies and their success on Amyotrophic Lateral Sclerosis study was discussed in recent review [33]. Also, the omics-era technologies for systems-level understanding of Streptomyceshas have been discussed in a recent review [34].…”

A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

“…These include protein aggregation, mitochondrial dysfunction, oxidative/nitrosative stress, endoplasmic reticulum (ER) stress, axonal transport defects, glutamate excitotoxicity, impaired macroautophagy, impaired glycolysis, neuroinflammation, and glucose and fat metabolism impairments [13][14][15][16][17][18][19]. However, hitherto no hypothesis exist that effectively links all these mechanisms to a singular central cause [3]. Hence, despite steadily accumulating knowledge about ALS, a key question still lingers: what cause ALS?…”

“…Amyotrophic lateral sclerosis (ALS) is the most feared, frequent, flummoxing and fatal motor neuron disease [1][2][3]. It is a biphasic disease which starts insidiously, later followed by relentless progression once symptomatic [4].…”

“…ALS pathology involves an interaction of multiple genes and environmental factors. Indeed, ALS is mainly a polygenic disease (70%-90); and the heritable form (familial) ALS contributes to merely 30% of total ALS cases [3,9]. Remarkably, mutant C9ORF72, TARDBP, FUS, and SOD1 genes account for 70% of all familial ALS cases [10].Evidence shows that environmental factors such as intense physical activity, cigarette smoking, viral infections, and the ingestion of non-protein amino acids (i.e.…”