Alternative splicing, a clever way in which a cell generates many different variations of messenger RNAs – single-stranded RNAs involved in protein synthesis – and proteins from the same part of DNA, plays an important role in molecular biology. Rapidly evolving, the field of alternative splicing is a complex subject and the scientific literature on this subject is already abundant.
David Nikomstudent at UC Riverside Neuroscience Graduate Programand his advisor, Sika Zhengassociate professor of biomedical sciences at UCR Medicine School and director of Center for RNA Biology and MedicineI wrote a goodbye in Nature Reviews Neuroscience to discuss emerging research and evidence for the role of alternative splicing defects in major neurodegenerative diseases. They also summarize the latest advances in RNA-based therapeutic strategies to target these disorders.
According to them, the topic of alternative splicing in neurodegenerative diseases is particularly relevant given the increasing frequency of neurodegenerative diseases worldwide and the urgent need for new approaches to their treatment and management. They argue that because aberrant splicing dysregulation frequently occurs in neurodegenerative diseases, the promise of using RNA-based therapies is important to understand and well suited for review.
Titled “Alternative splicing in neurodegenerative diseases and the promise of RNA therapies,” their review aims to provide comprehensive and comprehensive knowledge to a scientific audience interested in the subject. It synthesizes knowledge and discoveries from decades of research carried out by numerous laboratories around the world on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, frontal temporal dementia, and more. The work is supported by grants to Zheng from the National Institutes of Health. In the following questions and answers, Zheng and Nikom analyze key aspects of goodbye.
Q: What is alternative splicing deregulation?
Once a gene’s DNA is transcribed into pre-messenger RNA (RNA before it is spliced), only a small fraction of the pre-messenger RNA makes up the final messenger RNA transcript, or mRNA, which codes for the protein. Alternative splicing is a process by which a cell can select which of these protein-coding parts to include in the resulting RNA or protein. Dysregulation of alternative splicing occurs when this process goes wrong in some way. The cell chooses to include the wrong protein-coding parts or exclude some correct parts. This can cause all kinds of problems with the resulting protein: it might be shorter than it’s supposed to be, disrupting its normal function in the cell, or it might result in the protein not being produced at all.
Q: What role does alternative splicing play in molecular biology?
Alternative splicing greatly expands the diversity of proteins that can be made from a single gene. This is important because multicellular organisms make many different types of cells that make up the various types of tissues in their bodies. But each cell only has the same genetic code. To produce the dazzling complexity of multicellular life, cells depend on alternative splicing that gives them the flexibility to create large families of similar proteins with different tissue- and developmental-stage-specific functions. For example, some alternative splicing networks are only activated during embryonic development and shut down when the organism matures.
Q: In short, how does it contribute to the molecular pathology of a wide range of neurodegenerative diseases?
Some organs rely more than others on alternative splicing to generate cellular diversity. We don’t know why for sure, but the brain undergoes more alternative splicing than any other organ in the body. Scientists think this could be due to the brain’s unique complexity, its rapid evolution, or the extraordinary diversity of cell types it contains. What we do know is that there are many brain-specific alternative splicing events that occur systematically in neurological diseases. These include neurodevelopmental disorders, such as autism spectrum disorders, or neurodegenerative diseases, such as Alzheimer’s disease or ALS. The best-understood example we have so far concerns dysregulated alternative splicing in ALS. Scientists discovered that these erroneous splicing events led to the production of aberrant proteins or a reduction in normal proteins, which ultimately affected the health and function of neurons. Some other neurodegenerative diseases with dysregulated alternative splicing include frontotemporal dementia, Parkinson’s disease, familial dysautonomia, Huntington’s disease, spinal muscular atrophy, and Duchenne muscular dystrophy.
Q: Does alternative splicing play a role in other diseases?
Alternative splicing has been linked to approximately 15% of human genetic diseases and cancers. Mutations in components that regulate alternative splicing cause many diseases, both common and rare. Myotonic dystrophy, myelodysplastic syndromes (bone marrow cancers), degenerative retinal disorders such as retinitis pigmentosa, and progeria (a rare premature aging syndrome) are prominent examples of diseases caused by splicing defects.
Q: You conclude the review with the latest advances in RNA-based therapeutic strategies developed to target underlying splicing mechanisms. What are some of these advances?
A good example of targeting underlying splicing mechanisms to treat diseases is a disease called spinal muscular atrophy, a major genetic disorder in children and infants. Humans carry two nearly identical copies of the Survival Motor Neuron gene: SMN1 And SMN2 which are essential for the survival of all animal cells. Patients with spinal muscular atrophy lose SMN1; SMN2 is the only source of SMN protein in patients. The critical difference between SMN1 And SMN2 is the splicing of exon 7, a small fragment of protein-coding sequence in the SMN gene. Contrary to SMN1 exon 7, SMN2 exon 7 is generally not included in most tissues. The skipped exon 7 transcript generated by SMN2 produces a partially functional and unstable protein. The first therapeutic approval of SMA targets the SMN2 pre-mRNA and binds to a region accessed by the splicing machinery to remove exon 7. This ultimately leads to the blocking of exon 7 removal and promotes the formation of a functional SMN protein. By promoting the splicing of exon 7, this drug (Spinraza) increased the expression of SMN in the cell from SMN2 gene, compensating for the loss of SMN1and prevent cell loss in the central nervous system.
This story is a classic example of a splicing mechanism that can be targeted to treat an otherwise fatal disease in children. The hope is to understand more splicing mechanisms and find new ways to target them to treat other diseases.
Some of the latest advances:
- Splice-switching oligonucleotides (like Spinraza) for tauopathies – neurodegenerative disorders with abnormal deposition of tau protein – which can correct the balance of pathogenic isoforms (tau RNA variants) in the brain
- Splicing oligonucleotides targeting amyloid proteins that can reduce brain plaques in mice with Alzheimer’s disease
- Spliceosome-mediated RNA trans-splicing (SMaRT) – gene reprogramming system designed to correct aberrantly spliced mRNAs by replacing the entire coding sequence upstream or downstream of a splice site
- RNA-targeted CRISPR approaches that can reverse splicing defects without altering the patient’s genome like traditional gene therapies.
The header image shows David Nikom (left) and Sika Zheng. (UCR/Zheng Laboratory)
