Table 1.
Hallmarks of ageing in ALS
| Hallmarks of ageing | Cellular pathways implicated in ALS | Pathological protein involved | References |
|---|---|---|---|
| Primary hallmarks | |||
| Genomic Instability | Nuclear architecture alterations, nuclear pore pathology, damage to nuclear DNA, damage to mitochondrial DNA | SOD1, TDP-43, C9ORF72 DPRs, FUS, NEK1 | [47, 48, 58, 60, 63, 64, 332, 333] |
| Telomere attrition | Both shorter and longer telomeres are described in ALS | SOD1, C9ORF72 DPRs | [77, 334, 335] |
| Epigenetic alterations |
DNA hyper- and hypo-methylation, hyper- or hypo-acetylation of histones |
SOD1, FUS, TDP-43, C9ORF72 DPRs | [88, 95–97, 100, 228, 336] |
| Loss of proteostasis | Defects in protein folding, disrupted UPS, defective ER-Golgi trafficking, ER stress, Golgi fragmentation and defects in ERAD | SOD1, TDP-43, C9ORF72 DPRs, FUS | [102, 103, 337–340] |
| Dysregulated macroautophagy | Increased or decreased activation of autophagy, impaired mitophagy, dysregulated autophagy initiation and impaired autophagic flux | C9ORF72 DPRs, SOD1, TDP-43, TBK1, FUS, FIG4, OPTN, UBLN2, SQSTM1, CHMP2B, ALS2 | [341–348] |
| Antagonistic hallmarks | |||
| Cellular senescence | Microglia senescence, abnormal expression of senescence markers | SOD1, C9ORF72 | [174, 285, 349] |
| Mitochondrial dysfunction | Defects in membrane potential, decreased respiratory capacity, increased free radical production, reduced turnover, and dynamics | SOD1, TDP-43, C9ORF72 DPRs, UBQLN2 and FUS | [74, 191, 196, 332, 350–354] |
| Dysregulated nutrient sensing | Dysregulated mTOR signaling, AMPK pathway and SIRT regulation | SOD1, C9ORF72 DPRs, TDP-43 | [210, 220, 355, 356] |
| Integrative hallmarks | |||
| Impaired intercellular communication | Dysregulated interaction between glia and neurons, dysregulated EV and intracellular communication | SOD1, TDP-43, FUS and C9ORF72 DPRs | [244, 253, 357, 358] |
| Neuroinflammation |
Hyperactivated astrocytes and microglia, increased pro-inflammatory cytokines Changes in glia to proinflammatory phenotypes |
SOD1, TDP-43 | [359–361] |
| Stem cell exhaustion | Decreased functionality and regenerative capacity of NSCs | SOD1 | [362] |
| Dysbiosis |
Increased intestinal permeability to toxins, altered gut microbiota |
SOD1, C9ORF72 DPRs | [283, 284, 286] |
| Defects in RNA dysfunction |
RNA metabolic defects (RNA processing, modifications and transport), splicing defects, cryptic exon inclusion, dysregulated quality control of RNA such as NMD and RNA surveillance |
TDP43, FUS, TAF15 and hnRNPA1 | [62, 317, 363–366] |