Kartik Akkihal

Background:  Amyotrophic Lateral Sclerosis (ALS) is a fatal central nervous system (CNS) demyelination disease that impacts both upper motor neurons (UMNs) and lower motor neurons (LMNs). Classical clinical presentation is weakness starting in the limbs with both UMN and LMN signs. UMN symptoms include a positive Babinski reflex, spasticity, hyper-reflexivity. LMN symptoms include progressive weakness of voluntary skeletal muscles. Involvement of respiratory muscles can cause fatality.¹ The current management and treatment of ALS is severely limited, because of the variability in genotypes and phenotypes, but further understanding of pathophysiology can help develop specific treatment methods.^1,3 About 90% of ALS cases are sporadic, and more than 40 genes have been associated with ALS.^2,3 This paper highlights the SOD1 gene G93A mutation, and accumulation of abnormal mitochondria in relation to ALS.²

Objective: The purpose of this study was to look at mitochondrial dysfunction as one of the major determinants in ALS pathogenesis, highlighting the SOD1 gene. The SOD1 gene is a known factor that prevents astrocytes to maintain neuronal function and oxidant status, which makes it a good branch point for the development of potential therapies.³

Search Methods: PubMed searches were used with the terms “ALS,” “SOD1,” “pathogenesis,” “mitochondria,” and “treatments.” These search terms were used in various combinations. Only studies from the timeframe 2018-2024 were included in the search.

Results: The data from the overexpression of G93A mutation in skeletal muscle studies showed an enhanced intracellular ROS production.⁶ The authors used a mt-cpYFP in double transgenic mice as a marker to detect changes in ROS levels at the individual mitochondria level.⁶ Additionally, in the ALS-SOD1 mutant models, cGAS/DDX41-STING pathway is activated that increased type 1 interferon (IFN-I) signaling, and contributes to the progression of neurodegeneration in the autoimmune phenotype of ALS.⁵ The data indicated that the loss or inhibition of cGAS/STING signaling significantly extends lifespan and improves the functional performance of a mutant SOD1 disease model.⁵ Furthermore, ablation of Parkin (a mitochondrial ubiquitin ligase) delays ALS progression and elongates the survival of ALS-SOD1 mice by slowing down motor neuron loss and muscle denervation.⁷ In the spinal cord of ALS-SOD1 mice, the autophagy receptor p62 is recruited to damaged mitochondria and mitophagy is activated, depleting mitochondrial dynamics proteins, which are ubiquitinated by Parkin.⁷ The data from increasing dosage of R13 treatment showed that oxidative phosphorylation gene expression was increased over the course of a 90 day administration period in the SOD1 ALS animal models.⁴ R13 is a good example of a promising outlook for the treatment of SOD1 ALS animal models, and these experimental observations support that R13 can be explored for possible therapeutic use in ALS with similar mechanistic origins.¹

Conclusion: Studies have shown mitochondrial dysfunction is one of the major determinants in ALS pathogenesis, and the R13 prodrug improved the lifespan in ALS animal models via improving oxidative phosphorylation.  Thus, targeting mitochondrial dysfunction is a good starting point for the future of developing treatments for ALS.

Works Cited

1. Feldman EL, Goutman SA, Petri S, et al. Amyotrophic lateral sclerosis. Lancet. 2022;400(10360):1363-1380. doi:10.1016/S0140-6736(22)01272-7
2. Belosludtseva NV, Matveeva LA, Belosludtsev KN. Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis. Int J Mol Sci. 2023;24(23):16833. Published 2023 Nov 27. doi:10.3390/ijms242316833
3. Anderson G. Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides. Int J Mol Sci. 2022;24(1):587. Published 2022 Dec 29. doi:10.3390/ijms24010587
4. Li X, Chen C, Zhan X, et al. R13 preserves motor performance in SOD1G93A mice by improving mitochondrial function. Theranostics. 2021;11(15):7294-7307. Published 2021 May 24. doi:10.7150/thno.56070
5. Tan HY, Yong YK, Xue YC, et al. cGAS and DDX41-STING mediated intrinsic immunity spreads intercellularly to promote neuroinflammation in SOD1 ALS model. iScience. 2022;25(6):104404. Published 2022 May 13. doi:10.1016/j.isci.2022.104404
6. Xiao Y, Karam C, Yi J, et al. ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression. Pharmacol Res. 2018;138:25-36. doi:10.1016/j.phrs.2018.09.008
7. Palomo GM, Granatiero V, Kawamata H, et al. Parkin is a disease modifier in the mutant SOD1 mouse model of ALS. EMBO Mol Med. 2018;10(10):e8888. doi:10.15252/emmm.201808888