Targeting Histone Demethylase LSD1/KDM1a in Neurodegenerative Diseases

The autophagy-lysosome pathway sustains cellular homeostasis and is a protective mechanism against neurodegenerative diseases. Recent findings highlight the role of the histone demethylases LSD1/LDM1A as a pivotal regulator of autophagy process, by controlling the mTORC1 cascade, in neuroblastoma cells. LSD1 binds to the promoter region of the SESN2 gene, where LSD1-mediated demethylation leads to the accumulation of repressive histone marks that maintain SESN2 expression at low levels. LSD1 depletion results in enhanced SESN2 expression and consequently mTORC1 inhibition, thereby triggering the induction of autophagy. Our study provides important insight into neuroepigenetic mechanisms regulating the autophagic process, offering additional opportunities for the development of novel therapeutic strategies in diseases associated with dysfunctional autophagy-lysosomal pathway.