# Development of selective deconjugases for membrane-anchored LC3A/B in post-mitotic neurons

## TL;DR

Researchers developed specialized enzymes to target specific autophagy proteins in neurons, which could lead to new treatments for neurodegenerative diseases.

## Contribution

The study introduces deconjugases with enhanced selectivity for lipidated LC3A/B in post-mitotic neurons.

## Key findings

- Modifying LIRs at deconjugase termini improved targeting of LC3A/B.
- N-terminal LIR arrangements refined LC3A/B targeting without affecting GABARAP.
- Reducing α3 helix hydrophobicity enhanced selectivity for LC3A/B.

## Abstract

Neuronal autophagy is essential for maintaining protein and organelle turnover, thereby safeguarding neuronal health. LC3, a central autophagy protein, exists in lipidated (LC3-II) and non-lipidated (LC3-I) forms, both critical for neurons due to their sensitivity to metabolic and proteostatic stress. To elucidate the specific roles of membrane-anchored LC3A/B in post-mitotic neurons, we engineered deconjugases with enhanced selectivity for lipidated LC3. By modifying LC3-interacting regions (LIRs) at the deconjugase termini, we significantly improved targeting specificity toward LC3A/B. Deconjugases with N-terminal LIR modifications reduced LC3A/B-associated autophagosomes, highlighting the importance of LIR positioning for specificity. Sequential N-terminal LIR arrangements further refined LC3A/B targeting without affecting GABARAP-associated autophagosomes. Moreover, reducing the hydrophobicity of the α3 helix to limit membrane residence time further improved selectivity. These targeted modifications demonstrate the potential of customized deconjugases to dissect and modulate specific autophagic pathways in neurons, paving the way for novel therapeutic strategies against neurodegenerative diseases associated with autophagy dysregulation.