| TDP-43 proteinopathy | Found in ~95% of ALS cases (including sporadic), TDP-43 is an RNA-binding protein that forms cytoplasmic aggregates in affected neurons[@neumann2006] |
| FUS mutations | FUS (Fused in Sarcoma) is another RNA-binding protein mutated in some familial and rare sporadic ALS cases[@kwiatkowski2009] |
| Alternative splicing disruptions | Multiple ALS-linked genes regulate RNA splicing, suggesting this pathway may be a common vulnerability[@ling2013] |
| Neurofilament aggregation | Abnormal neurofilament accumulation is a hallmark of ALS motor neurons[@julien1998] |
| Axonal transport defects | Mutations in genes involved in axonal transport (e.g., DCTN1) are linked to ALS |
| Energy failure | Mitochondrial dysfunction leads to ATP depletion in motor neurons |
| Oxidative stress | Mitochondrial ROS production increases in ALS |
| Calcium buffering | Impaired mitochondrial calcium handling exacerbates excitotoxicity[@cozzolino2012] |
| Microglial activation | Pro-inflammatory microglia are abundant in ALS spinal cord |
| Astrogliosis | Reactive astrocytes surround motor neurons |
| Peripheral immune involvement | T cells and other immune cells infiltrate the CNS |
| Databases | OMIMOrphanetClinicalTrialsPubMed |