Regulation of mRNA Alternative Splicing and Surveillance in Normal and Pathological Conditions

Dear Colleagues,

Alternative pre-mRNA splicing generates multiple mRNA isoforms from a single gene, thereby expanding the proteome. During the cell life cycle, dynamic changes in alternative splicing play an important role in shaping the transcriptome. Hence, the physiological relevance and biological significance of RNA processing mechanisms, including alternative splicing, are attracting more research studies.

High throughput studies have provided a large amount of data, fueling our understanding of the role that mRNA metabolism plays in human diseases. However, mechanistic studies to deepen our knowledge of the pathophysiology are often missing. For instance, synonymous mutations or nucleotide variants in noncoding sequences are often overlooked; they may, however, be meaningful in developing altered phenotypes. Short sequences are indeed embedded in the pre-mRNA sequence and serve as RNA-binding sites for cell regulatory factors. Many splicing alterations observed in cancers, such as those found in myelodysplastic syndromes (MDS), result from mutations in pre-mRNA regulatory sequences, and mutations affecting the structure or the level of spliceosome components or non-spliceosomal splicing factors.

Alternative splicing regulation is particularly pervasive in neurons, and, therefore, these particular cells are highly sensitive to splicing perturbations. Neurodegenerative diseases are increasingly regarded as RNA-mediated diseases. In fact, aberrant splicing patterns are signature features in a growing number of diseases of the nervous system. Steady-state RNA levels result from the balance between regulated RNA synthesis and RNA turnover. Nonsense-mediated mRNA decay (NMD), an RNA surveillance mechanism, has recently drawn particular attention. The NMD pathway degrades some but not all mRNA molecules bearing premature termination codons (PTCs), to avoid the accumulation of toxic peptides. NMD mechanism is involved in neural stem cell differentiation, neural development, axon guidance, and synaptic plasticity. In humans, mutations in NMD components are associated with some forms of intellectual disability and neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. In seeking effective therapeutic strategies, recent advances using splicing or NMD inhibitors hold promise for treatment.

In this Special Issue, we welcome papers dealing with these issues. How mRNA processing mechanisms can contribute to cellular function in health and how their dysfunction triggers disease phenotypes, is the main aim of this Special Issue. Advances using complementary experimental and in silico approaches should provide insight into the role of alternative splicing as an important regulatory mechanism that helps to better understand the physiopathology of human diseases and to improve the development of therapeutic approaches.

Dr. Faouzi Baklouti
Guest Editor

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• pre-mRNA splicing
• mRNA decay
• NMD
• gene mutation
• inherited diseases
• neurodegenerative diseases
• hematologic malignancies
• solid tumor cancers