RNA Metabolism and Therapeutics in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder characterized by the selective death of upper and lowers motor neurons in spinal cord, brain stem, and motor cortex, which leads to paralysis and death within 2-3 years of onset. Deeply sequencing technologies, to simultaneously analyze the transcriptional expression of thousands of genes, offered new possibilities to focus on ALS pathogenesis and, most notably, to find new potential targets for novel treatments. The present book chapter illustrates recent advances in transcriptomic studies in animal models and human samples and in new molecular targets related to ALS pathogenesis and disease progression. Additionally, new insights into the involvement of altered transcriptional profiles of noncoding RNAs (microRNA and lncRNA) and ALS-associated ribosomal binding proteins have been investigated, to understand the functional consequences of extensive RNA dysregulation in ALS. Attention has been also turned on how transcriptome alterations could highlight new molecular targets for drug development.

Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases

“…Experimental findings show various disease mechanisms the transcript acts through, though it has a significant role in nuclear RNA sequestration, which directly impacts transcription [92]. LncRNA CCND1, a FUS-bound transcript and cell proliferation regulator, is another ncRNA associated with ALS, particularly through the Wnt/β-catenin signaling pathway [93][94][95]. FUS acts as an inhibitor to CCND1 expression to regulate cell cycle progression; however, its dysregulation may trigger apoptosis in ALS [96].…”

“…[92]. LncRNA CCND1, a FUS-bound transcript and cell proliferation regulator, is another ncRNA associated with ALS, particularly through the Wnt/β-catenin signaling pathway [93][94][95]. FUS acts as an inhibitor to CCND1 expression to regulate cell cycle progression; however, its dysregulation may trigger apoptosis in ALS [96].…”

Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases

“…Among the implicated pathological processes are protein aggregation, glutamate excitotoxicity, defects in stress response, mitochondrial dysfunction, protein aggregation, altered axonal transport, and aberrant RNA metabolism [ 199 , 200 , 201 ]. The role of this last, in particular, seems particularly central when considering that several ALS-linked genes, such as TARDBP or FUS , are key components of coding and noncoding RNA processing machinery [ 17 , 202 , 203 , 204 , 205 , 206 , 207 , 208 ].…”