Alternative Splicing: A Key Player in Gene Expression and Disease Pathogenesis

The relationship between the number of alternative spliced forms of genes and their diverse functions is a crucial aspect of genetic regulation and protein diversity. Alternative splicing, a process where a single gene can produce multiple proteins through different combinations of exons, significantly contributes to protein diversity in higher eukaryotes. This mechanism allows for the generation of multiple mRNA and protein products from a single gene, enhancing the functional complexity of organisms.

Research indicates that up to 95% of multi-exon genes in humans undergo alternative splicing, leading to proteins with diverse functions in distinct cellular contexts. Furthermore, around 15% of human hereditary diseases and cancers are linked to alternative splicing, highlighting its importance in disease etiology. Alternative splicing plays a crucial role in adaptive evolution by expanding transcriptomic and proteomic diversity, enabling different mRNA isoforms to be generated from the same gene.

The intricate regulation of alternative splicing involves various mechanisms and factors that interact to produce different isoforms. For instance, exon skipping is a common mode of alternative splicing where specific exons are included or excluded under different conditions or in specific tissues. Abnormal variations in splicing can lead to disease, with a significant proportion of human genetic disorders resulting from splicing variants

Role of Alternative Splicing in Gene Expression and Impact on Diseases
Alternative splicing (AS) is a fundamental regulatory process of gene expression that significantly enriches transcriptome content and promotes diversity in both transcriptome and proteome. This mechanism plays a pivotal role in cellular pathways of higher eukaryotes, allowing each gene to generate multiple mRNA variants, showcasing the evolutionary advantage of higher organisms.

Gene Expression:
- Transcript Diversity: AS enables the generation of multiple mRNA isoforms from a single gene, expanding transcriptomic diversity and contributing to the complexity of gene expression regulation.
- Protein Diversity: The diversity of proteins mediated by AS influences protein structure, function, interaction, and localization, playing a crucial role in the differentiation and development of various tissues and organs.

Impact on Diseases:
- Neurodegenerative Diseases and Autoimmune Diseases: AS and RBPs are associated with numerous neurodegenerative diseases and autoimmune disorders. Dysregulation of AS can contribute to disease pathogenesis by altering protein functionality and gene expression patterns.
- Cancer: Abnormalities in AS are linked to various diseases, particularly cancer. Changes in AS can lead to modifications in gene splicing patterns, resulting in alterations or loss of protein functionality. In cancer, aberrant AS and RNA-binding proteins (RBPs) may lead to the aberrant expression of cancer-associated genes, promoting tumor onset and progression.
- Regulation: The regulation of AS is a complex process involving various interacting components such as cis-acting elements, trans-acting factors, chromatin structure, RNA structure, alternative transcription initiation or termination sites. Any disruption in this process can lead to abnormal cellular functions and disease states.

Role of Alternative Splicing and RNA-Binding Proteins in Neurodegenerative and Autoimmune Diseases AS and RNA-binding proteins play crucial roles in the pathogenesis of neurodegenerative diseases and autoimmune disorders, such as multiple sclerosis (MS). Dysregulation of AS can lead to alterations in protein functionality and gene expression patterns, contributing to disease progression and neurodegeneration.

MS is a demyelinating, autoimmune, and neurodegenerative disease of the central nervous system (CNS), characterized by neuroinflammation and axonal injury.

Studies have shown that dysfunctional RBPs are associated with neurodegeneration in MS. Autoantibodies targeting RBPs like heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) have been linked to neuronal cell loss in MS, highlighting the impact of RBP dysfunction on disease pathogenesis.

Reference:
Jiang, W., & Chen, L. (2021). Alternative splicing: Human disease and quantitative analysis from high-throughput sequencing. Computational and structural biotechnology journal, 19, 183-195.
Singh, P., & Ahi, E. P. (2022). The importance of alternative splicing in adaptive evolution.
Wang, Y., Liu, J., Huang, B. O., Xu, Y. M., Li, J., Huang, L. F., ... & Wang, X. Z. (2015). Mechanism of alternative splicing and its regulation. Biomedical reports, 3(2), 152-158.
Tao, Y., Zhang, Q., Wang, H., Yang, X., & Mu, H. (2024). Alternative splicing and related RNA binding proteins in human health and disease. Signal Transduction and Targeted Therapy, 9(1), 26.
Libner, C. D., Salapa, H. E., & Levin, M. C. (2020). The potential contribution of dysfunctional RNA-binding proteins to the pathogenesis of neurodegeneration in multiple sclerosis and relevant models. International journal of molecular sciences, 21(13), 4571.