Abstract
It has been estimated that 80% of the pre-mRNA undergoes alternative splicing, which exponentially increases the flow of biological information in cellular processes and can be an attractive therapeutic target. It is a crucial mechanism to increase genetic diversity. Disturbed alternative splicing is observed in many disorders, including neuromuscular diseases and carcinomas. Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. Homozygous deletion in 5q13 (the region coding for the motor neuron survival gene (SMN1)) is responsible for 95% of SMA cases. The nearly identical SMN2 gene does not compensate for SMN loss caused by SMN1 gene mutation due to different splicing of exon 7. A pathologically low level of survival motor neuron protein (SMN) causes degeneration of the anterior horn cells in the spinal cord with associated destruction of α-motor cells and manifested by muscle weakness and loss. Understanding the regulation of the SMN2 pre-mRNA splicing process has allowed for innovative treatment and the introduction of new medicines for SMA. After describing the concept of splicing modulation, this review will cover the progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of SMA using the mechanism of alternative splicing.
Highlights
Splicing is an essential part of pre-mRNA maturation in a eukaryotic cell
Splicing reaction is controlled by the spliceosome, the macromolecular ribonucleoprotein complex
Specific sequences are recognized by the spliceosome, the macromolecular ribonucleoprotein structure that catalyses splicing [2]
Summary
That process consists of excising noncoding intronic sequences from the initial product of gene transcription and ligating remaining exons before translation to protein [1]. Due to tissue-specific RBPs bounding, final products from the same gene primary transcript can be different depending on the tissue. The tissue-specific RBPs bounding, final products from the same gene primary transcript can be different depending on the tissue The binding of these proteins is a variable process resulting in diverse combinations of included or excluded introns and exons [5]. The aim of this review is to present the novel forms of therapies of spinal muscular atrophy (SMA) based on alternative splicing regulation mechanisms
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