مقالات پذیرفته شده در هشتمین کنگره بین المللی زیست پزشکی
Amyotrophic Lateral Sclerosis (ALS): The Role of Key Genetic Mutations in Disease Progression
Amyotrophic Lateral Sclerosis (ALS): The Role of Key Genetic Mutations in Disease Progression
Sara Mehrabi,1,*
1. Department of Biology, Yadegar-e-Imam Khomeini Share Rey Branch, Islamic Azad University, Tehran, Iran
Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the weakening and wasting of voluntary muscles. Despite recent research, the diagnostic and treatment options remain unsatisfactory. About 90% of ALS cases are sporadic (sALS), while around 10% are familial (fALS). So far, 17 genes have been associated with ALS, with mutations in four key genes—SOD1, TARDBP, C9ORF72, and FUS—accounting for a large percentage of familial cases.
Research has shown that the C9ORF72 gene plays a significant role in ALS. Expansion of a GGGGCC hexanucleotide repeat in the noncoding region of this gene has been associated with behavioral and memory issues, as well as neurodegenerative disorders like ALS. It has been found that about 47% of fALS patients and 5% of sALS patients have this repeat expansion, making it the most frequent genetic cause of ALS so far.
Another important gene in ALS is SOD1, which encodes a protein found in various tissues like the liver and the central nervous system. Mutations in SOD1 are responsible for roughly 20% of fALS cases. There have been more than 180 mutations of SOD1 identified, accounting for about 3% of all ALS cases. These mutations cause the protein to misfold, leading to the formation of insoluble aggregates that spread between neurons, which contributes to the disease progression and nerve damage.
The FUS gene is another crucial gene in ALS. Although the exact mechanism of how FUS mutations cause neurodegeneration is still unclear, some evidence suggests that these mutations might affect processes like DNA repair, metabolism, and axonal transport, all of which could contribute to the progression of ALS.
Similarly, the TARDBP gene, which encodes the TDP-43 protein, is important for RNA metabolism. Mutations in TARDBP are linked to an increased risk of ALS and its progression. Abnormal TDP-43 has been found in all ALS cases, except in those with SOD1 and FUS mutations. Misfolded TDP-43 proteins form amyloid fibrils, which are a hallmark of ALS pathology.
Methods: To better understand how these genetic mutations contribute to ALS, we used model organisms such as fruit flies, zebrafish, and mice that were genetically modified to carry mutations in ALS-associated genes. We mainly focused on the processes of protein misfolding and aggregation. Using advanced microscopy and biochemical techniques, we observed the formation and spread of misfolded proteins in the neurons of these models. We also conducted behavioral tests to connect these molecular changes with functional impairments in the animals. These experiments were designed to compare the findings in animal models with the clinical features observed in human ALS patients.
Results: The main goal of these studies was to identify the genetic mutations that drive ALS progression. By using these animal models, we confirmed that a wide range of gene mutations, such as those in SOD1, TARDBP, C9ORF72, and FUS, play critical roles in ALS development.
Mutant SOD1 proteins were found to spread from one neuron to another in a prion-like manner, which accelerates the progression of the disease. Furthermore, C9ORF72 mutations were shown to lead not only to motor impairments but also to cognitive and behavioral abnormalities, which resemble the complex clinical symptoms observed in human ALS cases.
Our findings further confirmed that SOD1 mutations are a significant cause of familial ALS. We also demonstrated that C9ORF72 mutations are linked to both familial and sporadic ALS, emphasizing the diverse mechanisms underlying this complex disease.
Conclusion: In summary, the results of our research highlight the crucial role of genetic mutations in driving protein misfolding and aggregation in ALS. Mutations in genes like SOD1, TARDBP, C9ORF72, and FUS each affect different molecular pathways but all lead to the same devastating outcome—neurodegeneration.
Understanding these pathways is critical for developing future therapies aimed at targeting these misfolded proteins. Further research should focus on therapies that either prevent protein misfolding or stop the spread of aggregates between neurons. Translating these findings from animal models to human clinical treatments could pave the way for better therapeutic strategies for ALS patients in the future.