Targeting Autophagy-NAD Pathway Protects Cells in Niemann-Pick Type C1 Disease: Preclinical Findings

Synopsis

Impaired autophagy, which leads to the buildup of misfolded proteins and damaged organelles, has been linked to many human diseases. Loss of autophagy in metabolically active cells can cause metabolic collapse by depleting NAD+ pools, resulting in cell death. In cell models of Niemann-Pick type C1 (NPC1) disease, defective autophagy caused mitochondrial dysfunction, reduced both NAD+ and NADH levels, and triggered cell death. Screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators that restored NAD+ levels and cell viability. Either boosting autophagy pharmacologically or supplementing NAD+ precursors improved survival in NPC1 patient fibroblasts and iPSC-derived neurons. These findings highlight the autophagy-NAD+ axis as a key mechanism of cell death and a potential therapeutic target in NPC1 and other neurodegenerative disorders.

Journal

Cell Death & Disease