Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Autophagy impairment causes protein buildup and cell death, linked to diseases.
• Loss of autophagy in respiring cells depletes nicotinamide adenine dinucleotide (NAD) pools, causing metabolic collapse and cell death.
• Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder with impaired autophagy.

Purpose of the Study:

• To investigate the role of the autophagy-NAD axis in NPC1 disease pathogenesis.
• To identify therapeutic strategies for restoring cellular function and viability in NPC1 disease models.

Main Methods:

• Metabolic profiling to assess NAD levels in NPC1 cell models.
• Chemical screening to identify autophagy-activating drugs.
• Assessment of autophagic flux, mitochondrial function, and cell viability.
• Testing drug efficacy in NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons.

Main Results:

• NPC1 cells exhibit defective autophagic flux, impaired mitophagy, and subsequent depletion of NAD pools.
• NAD depletion leads to mitochondrial depolarization and apoptotic cell death in NPC1 cells.
• Celecoxib and memantine were identified as FDA-approved drugs that activate autophagy, restore NAD levels, and improve NPC1 cell viability.
• Pharmacological rescue of autophagy or NAD precursor supplementation improved NAD levels and viability in patient-derived cells and neurons.

Conclusions:

• The autophagy-NAD axis is a critical mechanism underlying cell death in NPC1 disease.
• Targeting the autophagy-NAD axis presents a promising therapeutic strategy for NPC1 disease.
• Findings suggest potential relevance for other neurodegenerative disorders involving autophagy dysfunction.