# NAD+ restores proteostasis through splicing-dependent autophagy

## TL;DR

NAD+ helps neurons by fixing splicing errors and boosting protein cleanup, which could help treat age-related brain diseases.

## Contribution

The study reveals a novel metabolic-transcriptional mechanism linking NAD+ to splicing-dependent autophagy in proteostasis.

## Key findings

- NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors.
- NAD+ rebalances EVA1C isoforms to enhance chaperone-assisted autophagy and proteasomal degradation.
- Loss of EVA1C impairs the memory and proteostatic benefits of NAD+ in neurons.

## Abstract

Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic – transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis through the NAD+ -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD+, underscoring its essential role in neuronal resilience. Mechanistically, NAD+ rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective macroautophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD+ restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic – transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.