Transcriptional Analysis Reveals Distinct Subtypes in Amyotrophic Lateral Sclerosis: Implications for Personalized Therapy

Abstract

Amyotrophic lateral sclerosis (ALS) is an incurable disease, caused by the loss of the upper and lower motor neurons. The lack of therapeutic progress is mainly due to the insufficient understanding of complexity and heterogeneity underlying the pathogenic mechanisms of ALS. Recently, we analyzed whole-genome expression profiles of motor cortex of sporadic ALS patients, classifying them into two subgroups characterized by differentially expressed genes and pathways. Some of the deregulated genes encode proteins, which are primary targets of drugs currently in preclinical or clinical studies for several clinical conditions, including neurodegenerative diseases. In this review, we discuss in-depth the potential role of these candidate targets in ALS pathogenesis, highlighting their possible relevance for personalized ALS treatments.

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

“…By using an unsupervised hierarchical clustering algorithm, we were able to separate, on the basis of their transcriptome profiles, control from SALS patients, subdividing these latter into two different groups (SALS1 and SALS2), each associated to specific differentially expressed pathways and genes (Aronica et al 2015). Interestingly, the analysis of altered networks of biological molecules in SALS provided a number of potential therapeutic targets, which could be used to interfere with ALS pathogenesis (Aronica et al 2015; Morello and Cavallaro 2015). …”

“…2a, Supplementary Table 1, and Supplementary Figs. 1a and 2a) (Aronica et al 2015; Morello and Cavallaro 2015). From this comparison, 19 statistically significant genes emerged as deregulated both in mice and SALS patients: 9 commonly altered with SALS1 and 16 with SALS2 patients (Fig.…”

“…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.…”