Autophagy-NAD Axis as a Target for Therapeutic Interventions in NPC1 Disease

Autophagy-NAD Axis as a Target for Therapeutic Interventions in NPC1 Disease


Targeting the autophagy-NAD axis has been reported be a viable therapeutic strategy for Niemann-Pick type C1 (NPC1) disease. The study suggests that both pharmacological rescue of autophagy deficiency and supplementation of NAD precursors can restore NAD+ level, improve the viability of fibroblasts in NPC1 patients, and induce pluripotent stem cell (iPSC)-derived cortical neurons.

About NPC1 disease 

Niemann-Pick disease, a hereditary chronic neurologic disorder, is categorized into three types, with NPC1 occurring in more different populations. NPC1 disease, an autosomal recessive disorder, is characterized by an enlarged spleen, neurological dysfunctions, and the accumulation of lipids such as sphingolipids and cholesterol. The disease is most commonly caused by mutations in the NPC1 gene which encodes a cholesterol transporter on the lysosomal membrane.

Targeting the autophagy-NAD axis: a promising approach for NPC1 disease

The loss of NPC1 function leads to impaired autophagy/mitophagy, resulting in NAD+ depletion, mitochondrial depolarisation, and apoptotic cell death. However, the use of autophagy inducers (celecoxib or memantine) and NAD precursors has shown promise in ameliorating the phenotypes observed in mouse and human NPC1 model cells.

Notably, NAD precursor supplementation acts downstream of autophagy dysfunction. Specifically, this supplementation promotes the viability of Npc1-/- MEFs and restores the apoptotic cell death in Npc1-/- cells, but exhibits no or mild upregulation of autophagy function in mouse embryonic fibroblasts (MEFs) and primary fibroblasts. However, autophagy activators not only rescue NAD depletion and cell death in Npc1-/- MEFs, but also restore autophagic flux and mitophagy deficit.

Targeting the autophagy-NAD axis can promote the survival of NPC1 patient-derived primary fibroblasts and protect against cell death of NPC1 patient iPSC-derived cortical neurons. Strikingly, boosting NAD+ level is believed to improve mitochondrial function and ATP generation, potentially replenishing lysosomal degradation capacity and restoring autophagic function in NPC1-mutant neurons.

                                NPC1 patient-derived primary fibroblasts

                             NPC1 patient iPSC-derived cortical neurons



Both autophagy inducers and NAD precursors are effective in ameliorating NPC1 disease, and combining the two may complement their strengths and maximize their effectiveness, opening new insights into the neurodegenerative conditions associated with autophagy and NAD+ defects.


Kataura T, Sedlackova L, Sun C, et al. Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models. Cell Death Dis. 2024;15(5):382. Published 2024 May 31. doi:10.1038/s41419-024-06770-y


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