NAD⁺ restores proteostasis through splicing-dependent autophagy

Area of Science:

• Neuroscience
• Molecular Biology
• Aging Research

Background:

• Autophagy declines with aging and neurodegeneration, impairing neuronal integrity.
• Nicotinamide adenine dinucleotide (NAD+) depletion is a hallmark of this decline, but its role in enhancing autophagic control is unclear.
• Alternative RNA splicing errors accumulate in aging brains, compromising proteostasis.

Purpose of the Study:

• To identify a metabolic-transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis.
• To investigate the role of the NAD+-EVA1C axis in neuronal resilience and age-related neurodegeneration.
• To explore NAD+ supplementation as a strategy to correct splicing errors and restore proteostasis.

Main Methods:

• Cross-species analyses in *C. elegans*, mice, and human samples.
• Investigated the effects of NAD+ supplementation on RNA splicing and EVA1C expression.
• Examined the interaction of EVA1C with chaperones BAG1 and HSPA/HSP70.

Main Results:

• NAD+ supplementation corrected hundreds of age- or Alzheimer-associated splicing errors, balancing EVA1C isoform expression.
• Loss of EVA1C impaired the memory and proteostatic benefits of NAD+.
• NAD+ rebalances EVA1C isoforms, enhancing chaperone-assisted selective macroautophagy and proteasomal degradation of misfolded proteins like tau.

Conclusions:

• NAD+ restoration coordinates RNA splicing fidelity with proteostatic systems via the NAD+-EVA1C axis.
• Metabolic splice-switching is a crucial mechanism for maintaining neuronal proteostasis.
• This study suggests new strategies targeting metabolic pathways for combating neurodegenerative diseases.