Metabolic stress-induced astrocytic senescence and neurotoxicity are driven by LRRK2-G2019S and reversible by LED Photobiomodulation

This aberrant interaction impedes the CUL4–DDB1-mediated proteasomal degradation of p21, leading to massive p21 accumulation, an exacerbated senescence-associated secretory phenotype (SASP), and subsequent neurodegeneration. Crucially, non-invasive LED-PBM dismantles this pathogenic axis by selectively disrupting the LRRK2–DDB1 interaction, thereby restoring p21 clearance and uncoupling metabolic dysfunction from neuronal injury.

Transcriptomic profiling via microarray was employed to unbiasedly interrogate global gene network alterations driven by the interaction between metabolic stress and the LRRK2-G2019S mutation