Molecular classification of amyotrophic lateral sclerosis by unsupervised clustering of gene expression in motor cortex

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, caused by the loss of motor neurons in the brain and spinal cord. Although 10% of ALS cases are familial (FALS), the majority are sporadic (SALS) and probably associated to a multifactorial etiology. Currently there is no cure or prevention for ALS. A prerequisite to formulating therapeutic strategies is gaining understanding of its etio-pathogenic mechanisms. In this study we analyzed whole-genome expression profiles of 41 motor cortex samples of control (10) and sporadic ALS (31) patients. Unsupervised hierarchical clustering was able to separate control from SALS patients. In addition, SALS patients were subdivided in two different groups that were associated to different deregulated pathways and genes, some of which were previously associated to familiar ALS. These experiments are the first to highlight the genomic heterogeneity of sporadic ALS and reveal new clues to its pathogenesis and potential therapeutic targets.

Selection and Prioritization of Candidate Drug Targets for Amyotrophic Lateral Sclerosis Through a Meta-Analysis Approach

“…In our previous work (Aronica et al 2015), we analyzed genes and pathway differentially deregulated in the motor cortex of two subgroups of SALS patients compared with controls. The analysis of altered networks of biological molecules in SALS has enabled to identify genes encoding potential therapeutic targets by combining various drug repositories (e.g., Metacore; Clinical Trials.gov; DrugBank; PubChem).…”

“…The analysis of altered networks of biological molecules in SALS has enabled to identify genes encoding potential therapeutic targets by combining various drug repositories (e.g., Metacore; Clinical Trials.gov; DrugBank; PubChem). In particular, we selected genes encoding proteins that were primary targets of drugs currently used in preclinical or clinical stages for treating several clinical diseases, giving greater emphasis to those that showed encouraging results for the treatment of neurodegenerative disorders (Aronica et al 2015; Morello and Cavallaro 2015). …”

“…To this regard, our research group has recently characterized the transcriptional profiles of motor cortex samples from SALS patients and differentiated these into two gene expression-based subgroups (SALS 1 and SALS2), revealing new clues to the molecular pathogenesis and novel potential predictive biomarkers and therapeutic targets (Aronica et al 2015; Morello and Cavallaro 2015). …”

“…The aim of the present study is to investigate the degree of conservation of the previously identified molecular targets (Aronica et al 2015; Morello and Cavallaro 2015) in SOD1 G93A transgenic mice, in order to prioritize their possible selection for a subsequent validation. The use of a meta-analytic approach offers a unique opportunity to significantly increase the statistical power of any individual microarray study, thus enabling identification of more reliable molecular biomarkers and targets.…”

Gene expression profiles and protein-protein interaction networks in amyotrophic lateral sclerosis patients with C9orf72 mutation

“…Though SALS and FALS are clinically and pathophysiologically similar, there is a requirement of finding the genes involved in FALS and the molecular mechanism pathways involved in the mutation of these genes. Till date studies were done to know the molecular mechanisms and underlying pathogenesis of ALS disease related to SALS with Superoxide dismutase 1 (SOD1) mutation [5, 6]. As the study of SOD1 has led to great advances in proper illustration of molecular mechanisms underlying in ALS disease, identifying the mutations in other genes and the pathways involved in these mechanisms is utmost important.…”