TABLE 2.
List of potential therapeutic targets.
| Gene1 | fALS2 | sALS2 | Protein family | Tissue enrichment3 | Proposed ALS mechanism |
| High-confidence (CNS) | |||||
| ADRA2B | 80% | 50% | GPCR | Low tissue specificity | Protein degradation |
| CYBB | 80% | 86% | Ion channel | Blood, lung, lymphoid tissue | Oxidative stress |
| FLT1* | 80% | 57% | Receptor kinase | Placenta | Inflammation |
| MAP3K5* | 80% | 71% | Protein kinase | Adrenal gland | Apoptosis |
| MAPK1 | 80% | 71% | CMGC kinase | Brain | Apoptosis |
| NOS1 | 80% | 86% | Oxidoreductase | Brain and skeletal muscle | Oxidative stress |
| NR3C1* | 80% | 86% | Nuclear receptor | Low tissue specificity | Inflammation, excitotoxicity |
| PTK2* | 40% | 86% | Tyrosine kinase | Low tissue specificity | Protein aggregation |
| PTPRC | 80% | 86% | Receptor phosphatase | Blood, lymphoid tissue | Inflammation |
| RARA | 50% | 14% | Nuclear receptor | Low tissue specificity | Neurogenesis |
| Novel (CNS) | |||||
| AHCYL1 | 100% | 71% | Enzyme | Low tissue specificity | Apoptosis |
| KCNB2 | 60% | 83% | Ion channel | Brain, lymphoid tissue, pituitary gland | Excitotoxicity |
| P2RY14 | 40% | 14% | GPCR | Granulocytes, dendritic cells, placenta | Inflammation |
| SCYL1 | 40% | 14% | Protein kinase | Low tissue specificity | Apoptosis |
| SLC25A10 | 20% | 29% | Transporter | Liver | Oxidative stress |
| STUB1* | 20% | 14% | Acyltransferase | Low tissue specificity | Protein degradation |
| High-confidence (diMN) | |||||
| DNMT3A | 0.1324 (0.0346) | 0.0773 (0.1172) | Methyltransferase | Low tissue specificity | Apoptosis |
| ERN1 | 0.2058 (0.003) | 0.0699 (0.1644) | Protein kinase | Low tissue specificity | Protein aggregation, apoptosis |
| G6PD# | −0.1416 (0.0487) | −0.0847 (0.1337) | Oxidoreductase | Testis | Oxidative stress |
| HSPD1*# | 0.1363 (0.1365) | 0.1916 (0.0083) | Isomerase | Vagina | FUS pathology, inflammation |
| PPIA*# | 0.1728 (0.0338) | 0.2361 (0.0003) | Isomerase | Low tissue specificity | TDP-43 pathology, inflammation |
| RPS6KB1 | 0.1558 (0.0297) | 0.1426 (0.0052) | AGC kinase | Low tissue specificity | Protein aggregation |
| VCP*# | 0.0212 (0.637) | 0.0776 (0.0411) | Hydrolase | Low tissue specificity | Mitochondrial dysfunction |
| Novel (diMN) | |||||
| KCNS3 | 0.3886 (0.0995) | 0.3338 (0.0282) | Ion channel | Skeletal muscle | Excitotoxicity |
| PPP3CB# | −0.3048 (0.0115) | −0.1371 (0.1725) | Esterase | Skeletal muscle | Protein aggregate degradation |
| PSMC6# | −0.2636 (0.0402) | −0.1502 (0.0926) | Hydrolase | Low tissue specificity | Proteostasis |
| METTL21A | 0.196 (0.0012) | 0.0827 (0.0432) | Methyltransferase | Low tissue specificity | Protein aggregation |
| TOPORS | 0.2161 (0.0135) | 0.1385 (0.0184) | Acyltransferase | Low tissue specificity | Apoptosis |
1Manually curated aging-associated genes (marked with *) based on clinical trials (https://clinicalTrials.gov/), publication, geroprotectors (http://geroprotectors.org) and GenAge database (https://genomics.senescence.info/genes/index.html); for the diMN targets, targets identified using proteomic data are marked with #;
2Shown for CNS targets are percentages of comparisons with up-regulated target (LFC > 0) out of five fALS or seven sALS comparisons; Shown for diMN targets are LFC and p-value in parenthesis;
3Tissue enrichment (RNA) retrieved from Human Protein Atlas (https://www.proteinatlas.org/) on November 15, 2021.