Mechanisms of microglial senescence in ALS: causative vs consequential roles

What is the causal relationship between microglial senescence and ALS progression? Do senescent microglia actively drive motor neuron loss, or do they accumulate as a secondary consequence of neurodegeneration? Key sub-questions: (1) Are there molecular signatures that distinguish senescent microglia in ALS vs normal aging? (2) Can senolytic interventions slow disease progression in ALS models? (3) What role does SASP (senescence-associated secretory phenotype) play in ALS neuroinflammation? (4) Is TREM2 signaling in microglia protective or pathogenic in ALS? (5) How does C9orf72 repeat expansion affect microglial activation states?