Why Alternative Splicing is Important in Neurodegenerative Diseases and Potential Therapeutic Strategies
Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and ALS, pose a significant health burden in society. These diseases are characterized by the progressive loss of neurons, leading to various neurological symptoms. In recent years, researchers have been increasingly interested in understanding the role of alternative splicing dysregulation in the pathogenesis of these disorders. Alternative splicing is a cellular process that allows for the generation of multiple protein variants from a single gene. This process plays a crucial role in molecular biology as it greatly expands the diversity of proteins that can be produced.
Alternative splicing dysregulation occurs when the process goes awry, resulting in the inclusion or exclusion of incorrect protein-coding parts in the RNA or protein. In neurodegenerative diseases, this dysregulation has been observed consistently and is believed to contribute to the molecular pathology of these conditions. It leads to the production of aberrant proteins or the reduction of normal proteins, ultimately affecting neuronal health and function.
The brain, in particular, relies heavily on alternative splicing to generate cell diversity. It has been found that the brain exhibits more alternative splicing events than any other organ in the body. This high degree of alternative splicing may be due to the complex nature of the brain, its rapid evolution, or the diverse range of cell types it contains. Regardless of the exact reasons, it is clear that alternative splicing plays a significant role in brain development and function.
To address the increasing prevalence of neurodegenerative diseases and the urgent need for new treatment approaches, researchers have turned to RNA-based therapeutic strategies. These strategies aim to target the underlying splicing mechanisms and correct the dysregulation associated with these disorders. One example of a successful RNA-based therapy is Spinraza, which is used to treat spinal muscular atrophy (SMA), a genetic disease affecting children and infants. Spinraza promotes exon 7 splicing, leading to the production of functional SMN protein and preventing cell loss in the central nervous system.
In addition to Spinraza, there have been other recent advances in RNA-based therapeutic strategies for neurodegenerative diseases. These include the use of splice change oligonucleotides to correct the balance of disease-causing isoforms in tauopathies, the targeting of amyloid proteins to reduce brain plaques in Alzheimer’s, and the development of RNA-targeted CRISPR approaches to reverse splicing defects.
Overall, alternative splicing dysregulation plays a significant role in the molecular pathology of neurodegenerative diseases. By understanding and targeting the underlying splicing mechanisms, researchers are making strides in developing effective RNA-based therapies. These advancements offer hope for better treatment and management of these devastating disorders, bringing us closer to finding a cure.
Summary:
Alternative splicing dysregulation in neurodegenerative diseases is a topic of growing interest in scientific research. Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and ALS, involve the progressive loss of neurons and have a significant impact on society. Alternative splicing is a cellular process that allows for the generation of multiple protein variants from a single gene, greatly expanding the diversity of proteins produced. However, dysregulation of alternative splicing can lead to the production of aberrant proteins or the reduction of normal proteins, contributing to the molecular pathology of neurodegenerative diseases.
The brain exhibits a high degree of alternative splicing and relies on this process for generating cell diversity. The reasons for this increased splicing complexity in the brain are not yet fully understood, but it is clear that alternative splicing plays a crucial role in brain development and function. Researchers have recognized the importance of alternative splicing dysregulation in neurodegenerative diseases, considering the increasing prevalence of these conditions worldwide and the urgent need for new treatment approaches.
RNA-based therapeutic strategies have emerged as promising avenues for addressing alternative splicing dysregulation in neurodegenerative diseases. One example is the use of Spinraza to treat spinal muscular atrophy, which promotes exon splicing to produce functional SMN protein. Other advances include the development of splice change oligonucleotides, splicing-mediated RNA trans-splicing systems, and RNA-targeted CRISPR approaches. These strategies aim to correct splicing defects and restore proper protein production, offering hope for better disease management and potential cures.
Overall, alternative splicing dysregulation in neurodegenerative diseases is a complex and rapidly progressing field. By understanding the role of alternative splicing in these disorders and developing RNA-based therapeutic strategies, researchers are making significant strides towards improved treatment approaches and better management of these devastating diseases.
Additional piece:
Alternative splicing dysregulation: Unlocking the Potential for Precision Medicine in Neurodegenerative Diseases
Neurodegenerative diseases continue to pose immense challenges to healthcare systems worldwide. The increasing prevalence of these disorders, coupled with the lack of effective treatment options, calls for innovative approaches to tackle the underlying molecular mechanisms. Alternative splicing dysregulation has emerged as a promising target for precision medicine in neurodegenerative diseases, offering new avenues for therapeutic intervention.
Alternative splicing, a cellular process that allows for the production of multiple protein variants from a single gene, plays a critical role in molecular biology. It provides cells with the flexibility to create diverse proteins with tissue- and developmental-stage-specific functions, contributing to the complexity of multicellular organisms. In neurodegenerative diseases, dysregulation of alternative splicing leads to the production of aberrant proteins or the reduction of vital proteins, disrupting neuronal health and function.
Understanding the molecular basis of alternative splicing dysregulation in neurodegenerative diseases is crucial for developing targeted therapies. Researchers have made significant progress in elucidating the splicing events associated with specific disorders, such as Alzheimer’s, Parkinson’s, and ALS. By identifying the key splicing factors and regulatory elements involved, they have laid the foundation for the development of RNA-based therapeutic strategies.
RNA-based therapies hold great promise in correcting alternative splicing dysregulation. Splice change oligonucleotides, such as Spinraza, have demonstrated success in restoring proper splicing patterns in diseases like spinal muscular atrophy. These therapies work by targeting specific regions of RNA molecules and influencing the splicing process to produce functional proteins.
Recent advances in RNA-targeted CRISPR approaches offer further possibilities for precision medicine in neurodegenerative diseases. By using the gene-editing capabilities of CRISPR technology, researchers can potentially correct splicing defects without altering the patient’s genome. This approach holds tremendous potential for treating diseases caused by specific splicing mutations, providing a tailored solution for individual patients.
In addition to therapeutic strategies, alternative splicing dysregulation can also serve as a potential diagnostic biomarker for neurodegenerative diseases. By analyzing the splicing patterns of specific RNA molecules, researchers may be able to identify early markers of disease progression and personalize treatment options based on a patient’s splicing profile.
While alternative splicing dysregulation presents exciting opportunities for precision medicine in neurodegenerative diseases, challenges lie ahead. Further research is needed to fully understand the complexity of alternative splicing networks and their dysregulation in specific diseases. Additionally, the development of safe and efficient delivery systems for RNA-based therapies is essential for their successful translation into clinical practice.
In conclusion, alternative splicing dysregulation represents a significant area of research in the field of neurodegenerative diseases. By harnessing the power of RNA-based therapies and precision medicine approaches, there is hope for developing novel treatments that can address the underlying molecular pathology of these devastating disorders. Continued efforts in this field have the potential to transform the landscape of neurodegenerative disease management and ultimately improve the lives of millions of patients worldwide.
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Alternative splicing, a clever way for a cell to generate many different variations of messenger RNAs (single-stranded RNAs involved in protein synthesis) and proteins from the same stretch of DNA, plays an important role in molecular biology. Progressing rapidly, the field of alternative splicing is a complex topic and the scientific literature on it is already extensive.
David Nikom, a student in the UC Riverside Neuroscience Graduate Program, and his advisor, Sika Zheng, an associate professor of biomedical sciences at the UCR School of Medicine and director of the RNA Center for Biology and Medicine, have written a review in Nature Reviews Neuroscience to discuss emerging research and evidence for the roles of alternative splicing defects in major neurodegenerative diseases. They also summarize the latest advances in RNA-based therapeutic strategies to address these disorders.
According to them, the issue of alternative splicing in neurodegenerative diseases is particularly relevant in view of the increasing frequency of neurodegenerative diseases worldwide and the urgent need for new approaches to their treatment and management. They argue that since aberrant splicing dysregulation commonly occurs in neurodegenerative diseases, the promise of using RNA 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 for a scientific audience interested in the topic. It synthesizes the knowledge and discoveries of decades of research carried out by many laboratories around the world on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, temporal frontal dementia, etc. The work is supported by grants to Zheng from the National Institutes of Health.
In the following Q&A, Zheng and Nikom reveal key aspects of the review.
Q: What is alternative splicing dysregulation?
Once the DNA of a gene is transcribed into pre-messenger RNA (RNA before it is spliced), only a small fraction of the pre-messenger RNA becomes the final messenger RNA transcript, or mRNA, that encodes the gene. protein. Alternative splicing is a process by which a cell can select which of those protein-coding parts to include in the resulting RNA or protein. Alternative splicing dysregulation is when this process goes awry in some way. The cell chooses to include the wrong parts of protein coding or to exclude some of the correct parts. This can cause all sorts of problems with the resulting protein: it could be shorter than it’s supposed to be, disrupting its normal function in the cell, or it could cause the protein to not be made at all.
P: What role does alternative splicing play in molecular biology?
Alternative splicing greatly expands the diversity of proteins that can be produced from a single gene. This is important because multicellular organisms produce so many different types of cells that make up the various types of tissues in your body. But each cell just 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, certain alternative splicing networks are only activated during embryonic development and close when the organism matures.
P: Briefly, how does it contribute to the molecular pathology of a wide range of neurodegenerative diseases?
Certain organs depend on alternative splicing to generate cell diversity more than others. We don’t know why for sure, but the brain has more alternative splicing than any other organ in the body. Scientists speculate that this could be due to the unique complexity of the brain, 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 consistently go awry in neurological diseases. These include neurodevelopmental disorders, such as autism spectrum disorder, or neurodegenerative diseases, such as Alzheimer’s disease or ALS. The best understood example we have so far has to do with deregulated alternative splicing in ALS. The scientists discovered that these missplicing events lead to the production of aberrant proteins or the reduction of normal proteins, ultimately affecting neuronal health and function. 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.
P: 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 the components that regulate alternative splicing are the cause of many diseases, both common and rare. Myotonic dystrophy, myelodysplastic syndromes (bone marrow cancers), retinal degenerative disorders such as retinitis pigmentosa, and progeria (rare premature aging syndrome) are leading 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 disease is a disease called spinal muscular atrophy, a major genetic disease of 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 have loss of SMN1; SMN2 it is the only source of SMN protein in patients. The critical difference between SMN1 and SMN2 it is the splice of exon 7, a small fragment of the protein-coding sequence within the SMN gene. Unlike SMN1 exon 7, SMN2 exon 7 is not usually included in most tissues. The skipped transcript of exon 7 generated by SMN2 produces a partially functional and unstable protein. The first therapeutic approval for SMA goes to the SMN2 pre-mRNA and binds to a region accessed by the splicing machinery to delete exon 7. This ultimately leads to blockade of exon 7 deletion and promotes the formation of functional SMN protein. By promoting exon 7 splicing, this drug (Spinraza) increased SMN expression in the cell from the SMN2 gene, compensating for the loss of SMN1and preventing cell loss in the central nervous system.
This story is a textbook example of a splicing mechanism that can be used to treat an otherwise fatal disease in children. The hope is to understand many more splicing mechanisms and find new ways to address them to treat other diseases.
Some of the latest advances:
- Splice change oligonucleotides (such as Spinraza) for tauopathies (neurodegenerative disorders with abnormal deposition of tau protein) that can correct the balance of disease-causing isoforms (tau RNA variants) in the brain
- Splicing oligonucleotides targeting amyloid proteins may reduce brain plaques in Alzheimer’s mice
- Splicing-mediated RNA trans-splicing (SMaRT): gene reprogramming system designed to correct aberrant 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.
https://www.sciencedaily.com/releases/2023/06/230620174504.htm
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