Amyotrophic Lateral Sclerosis (ALS): CCS and SOD2 interactions with SOD1 leading to progression

Abstract

This project investigates the genetic and molecular mechanisms contributing to Amyotrophic Lateral Sclerosis (ALS). ALS, a fatal neurodegenerative disorder, leads to the degeneration of motor neurons, resulting in muscle weakness, loss of motor control, and eventual respiratory failure. The study focuses on the interactions between the SOD1 gene and proteins CCS (Copper Chaperone for Superoxide Dismutase) and SOD2 (Superoxide Dismutase 2), which play crucial roles in protein folding, oxidative stress regulation, and mitochondrial function. Mutations in the SOD1 gene lead to protein misfolding, aggregation, and toxicity, disrupting cellular processes. CCS delivers copper ions to SOD1, aiding its maturation, while SOD2 mitigates oxidative damage in mitochondria. Mutations in CCS hinder copper binding, increasing SOD1 aggregation and cytoplasmic toxicity. The research highlights the limitations of current therapies, including Tofersen, an FDA-approved gene therapy targeting SOD1. While Tofersen reduces neurodegeneration markers, it only slows disease progression rather than offering a cure. Future research directions include exploring CRISPR/Cas9-mediated gene therapies for personalized treatment and focusing on the overlooked role of SOD2 in ALS pathology. Advancing understanding of these protein interactions could lead to more effective therapeutic interventions and improved outcomes for ALS patients.

C9orf72 gene is located in chromosome 9
(Figure representation created by the authors:Kayla Roh and Tarun Chethan)

Background

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal neurological disorder characterized by the degeneration and hardening (sclerosis) of motor neurons. This progressive deterioration severely impairs muscle control, ultimately leading to the loss of essential functions such as speaking and breathing. Traditionally, ALS has been classified into two categories: “familial” and “sporadic.” Although sporadic ALS accounts for 90–95% of cases, the term "sporadic" is somewhat misleading, as it still exhibits an estimated 50% heritability. Consequently, regardless of its classification, ALS generally demonstrates a consistent genetic component in its underlying causes.

Problem Statement

Over 30 genes have been identified as playing a role in the development of both types of ALS. The SOD1, or superoxide dismutase mutation, commonly affects 10-20% of familial ALS cases, and is also observed to be present in 1-2% of sporadic ALS cases as well. We have observed in this study that SOD1 typically has various interactions with other genes and their corresponding proteins, such as SOD2 and CCS, that will require further study and analysis.

Research Hypothesis

Amyotrophic Lateral Sclerosis is a disease with a polygenic spectrum of mutations and maladaptations. Genes such as SOD1, C9orf72, FUS and TARDBP are well known and have been deeply studied within their interactions with ALS disease progression. Identifying novel genes that interact and affect the functioning of these genes will further our understanding of the disease and help develop novel therapies to cure it.

Results

Mechanism of how CCS affects SOD1 and leads to the aggregation of SOD1.
(Figure representation created by the authors:Kayla Roh and Tarun Chethan)

We analyzed results from the GWAS studies and identified CCS1 and SOD2 as genes interaction with SOD1. SOD2 is not well studied despite having the connections observed with SOD1, which is clearly acknowledged to play a vital role in the development of ALS. The CCS gene delivers copper to SOD2, activating the antioxidant function of SOD2. Mutations or risk snps in either gene build up oxidative stress, increasing cellular damage and elevating the risk of ALS development. SOD2 primarily functions in mitochondria, while SOD1 operates in the cytosol; both collaboratively mitigate oxidative stress by detoxifying superoxide radicals. We also researched recently approved gene therapy for ALS called Tofesen. Given the benefits and limitations seen from the already-existing Tofersen treatment, it can be observed that there is still a lot of work that needs to be done in the study of each case of ALS and their unique intricacies, though progress is currently being made and hopefully, more advancements and breakthroughs will continue to be found.

DAVID demonstrates a strong correlation of SOD2 and CCS with development of ALS.

Conclusion

Various factors can lead to ALS, both on a genetic and environmental scale.However the exact cause for many of ALS cases is not very well understood as there is limited research in the field. As a result, disease continues to be largely misunderstood and overlooked. Tofersen is a gene therapy recently approved for treatment of SOD1 mutated patients of ALS. Tofersen also has several shortcomings and offers a solution only for SOD1 mutant ALC, there is a need to understand other risk factors and identify good treatment for management of ALS. We identified CCS and SOD2 as other genes that are functionally linked to SOD1 and therefore mutation in these genes can also lead to ALS. To conclude, further research is to be conducted to understand the underlying causes and thereby suitable treatment for ALS patients.