Introduction. Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a 2-5 year prognosis that starts with limb and/or speech paralysis that progresses to the respiratory muscles, eventually leading to death1. Treatment is supportive and diagnosis is made by exclusion, therefore there is a need for biomarkers that can screen for ALS and track disease progression1,2,3. ALS can be familial or sporadic, with majority of cases being sporadic2. Superoxide dismutase 1 (SOD1) is an antioxidant protein present on the ALS1 gene locus that’s classically been studied in familial ALS, with loss-of-function mutations increasing intracellular reactive oxygen species (ROS) and gain-of-function mutations causing SOD1 aggregation, causing neurotoxicity4. TDP-43, a nuclear RNA-binding protein, and VAPB, an integral membrane protein at the ALS8 locus, aggregate in both familial and sporadic ALS4,5. Methods. CRISPR/Cas9-mediated genome editing of SOD1 was performed in C. elegans to produce single-copy/knock-in models to determine differences in neuronal specificity for loss-of-function versus gain-of-function SoD1 mutations6. To induce VAPB aggregation, a P56S missense mutation was introduced into Drosophila models5. Drosophila lacking SOD1 were used to see if increased ROS affected VAPB aggregates5. Urate, a potential antioxidant, was explored in mutant hSOD1 cell and Drosophila models of ALS3. SOD1’s use as a biomarker was studied by using a 7-amino acid endogenous peptide in CSF of human SOD1 mutation carriers2. Antisense oligonucleotide-mediated SOD1 silencing was explored as a therapy for gain-of-function SOD1 mutations2. Results. Percent intact glutamatergic neurons in ALS model animals decreased significantly after oxidative stress exposure6. In gain-of-function SOD1 models, oxidative stress caused degeneration of cholinergic motor neurons6. VAPB aggregates decreased when SOD1 levels were reduced in Drosophila brains, suggesting that ROS may clear VAPB aggregates5. Urate upregulated the Akt pathway, increasing synthesis of Glutathione (GSH), an antioxidant, which attenuated mutant hSOD1 elevations in ROS3. SOD1 peptide levels were elevated in rats and human subjects with gain-of-function mutations2. ASO SOD1 silencing decreased SOD1 translation and decreased SOD1 levels in neurons of rat models of ALS2. Conclusions. The mutation type at the ALS1 locus indicates specificity for neuronal degeneration6. Intracellular levels of SOD1 can influence aggregation of VAPB, with decreased SOD1 levels leading to ROS-mediated clearance of VAPB aggregates5. Urate should be further explored as a therapy to reduce ROS-mediated damage of motor neurons in ALS3. Additionally, screening methods such as SOD1 peptide levels in CSF should be further assessed for validity since there is no current screening method2.
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- Gertsman I, Wuu J, McAlonis-Downes M, et al. An endogenous peptide marker differentiates SOD1 stability and facilitates pharmacodynamic monitoring in SOD1 amyotrophic lateral sclerosis. JCI Insight. 2019;4(10). doi:10.1172/jci.insight.122768
- Zhang C, Yang Y, Liang W, et al. Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3β/Nrf2/GCLC pathways. Brain Research Bulletin. 2019;146:287-301. doi:10.1016/j.brainresbull.2019.01.019
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- Chaplot K, Pimpale L, Ramalingam B, Deivasigamani S, Kamat SS, Ratnaparkhi GS. SOD1 activity threshold and TOR signaling modulate VAP(P58S) aggregation via reactive oxygen species-induced proteasomal degradation in a <em>Drosophila</em> model of amyotrophic lateral sclerosis. Dis Models Mech. 2019;12(2):dmm033803. doi:10.1242/dmm.033803
- Baskoylu SN, Yersak J, O’Hern P, et al. Single copy/knock-in models of ALS SOD1 in C. elegans suggest loss and gain of function have different contributions to cholinergic and glutamatergic neurodegeneration. PLoS Genet. 2018;14(10):e1007682. Published 2018 Oct 8. doi:10.1371/journal.pgen.1007682