The role of long noncoding RNAs in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a poor prognosis leading to death. The diagnosis and treatment of ALS are inherently challenging due to its complex pathomechanism. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides involved in different cellular processes, incisively gene expression. In recent years, more studies have been conducted on lncRNA classes and interference in different disease pathologies, showing their promising contribution to diagnosing and treating neurodegenerative diseases. In this review, we discussed the role of lncRNAs like NEAT1 and C9orf72-as in ALS pathogenesis mechanisms caused by mutations in different genes, including TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), superoxide dismutase type 1 (SOD1). NEAT1 is a well-established lncRNA in ALS pathogenesis; hence, we elaborate on its involvement in forming paraspeckles, stress response, inflammatory response, and apoptosis. Furthermore, antisense lncRNAs (as-lncRNAs), a key group of transcripts from the opposite strand of genes, including ZEB1-AS1 and ATXN2-AS, are discussed as newly identified components in the pathology of ALS. Ultimately, we review the current standing of using lncRNAs as biomarkers and therapeutic agents and the future vision of further studies on lncRNA applications.

Transcriptional profiling of human brain cortex identifies novel lncRNA-mediated networks dysregulated in amyotrophic lateral sclerosis

“…Several tools for studying lncRNAs have been developed so far 33 , but a comprehensive understanding of their role and involvement in human diseases is still lacking. Despite a very few reports mentioned a role or a function directly attributed to lncRNAs in this disease 21,22,34,35 , some authors recently reported a differential expression of lncRNAs in ALS transcriptomic data. For instance, RNA sequencing performed on cervical, thoracic and lumbar regions from post-mortem ALS patients, displayed a statistically significant down-regulation of lncRNAs in ALS patients, accounting for almost 55% of all the down-regulated genes and 15% of the up-regulated ones 36 .…”

“…The involvement of RNA processing, metabolism and regulation in ALS pathogenesis has been described by numerous reports [14][15][16][17][18][19][20] , and the importance of ribostasis -the appropriate production and regulation of the cellular transcriptome -is further confirmed by the fact that many neuromuscular and neurodegenerative disorders are associated to alterations in protein folding, RNA regulation, RNA binding proteins, or RNP aggregates 17 . Such a scenario implies that distinct, yet uncovered, "molecular regulators" could be involved in ALS pathogenesis, including long non-coding RNAs (lncRNAs) 21,22 a novel class of transcripts whose main function relies on the regulation of biological functions related to cell differentiation and regeneration [23][24][25][26] . By definition, they are non-coding transcripts longer than 500 nucleotides, mostly generated by the RNA-Pol II 27 .…”