Mechanistic Study of Neurodegenerative Disease-Associated Genes in Regulating Cellular Autophagy

Cellular autophagy, a conserved degradation mechanism in eukaryotic cells, plays a pivotal role in eliminating misfolded proteins and damaged organelles, with its dysfunction closely linked to the pathogenesis of neurodegenerative diseases. This study investigates seven pathogenic genes of neurodegenerative diseases (hnRNPA1, hnRNPA2B1, CHCHD10, Pfn1, Nefh, DAO, and DNAJC6) that have not been previously reported in relation to autophagy. To investigate their functional role in autophagy, we systematically explored their regulatory effects on the autophagic pathway by using siRNA interference, pathogenic mutant overexpression, and CRISPR/Cas-9 gene knockout techniques.The results show that knockdown of hnRNPA1, hnRNPA2B1, and CHCHD10 specifically induces the accumulation of the autophagic substrate p62 in neurons and inhibits autophagosome formation and maturation. Overexpression of the Pfn1 E117G mutant also significantly impairs autophagic progression. Gene knockout experiments demonstrate that deletion of hnRNPA1 and hnRNPA2B1 reduces the LC3-II/I ratio, thereby inhibiting autophagy, while DAO gene knockout promotes autophagy by increasing the LC3-II/I ratio. These findings reveal a novel mechanism by which neurodegenerative disease pathogenic genes participate in disease development through autophagy regulation, providing important evidence for elucidating the pathological basis of related diseases and developing autophagy-targeted therapeutic strategies.