# Cell type‐specific regulation of m6A modified RNAs in the aging Drosophila brain

## TL;DR

This study explores how RNA modifications called m6A change in aging fruit fly brains and how these changes affect neurons and glial cells differently.

## Contribution

The study reveals that m6A modification has opposing effects in neurons versus glia during aging and disease, with Mettl3 knockdown improving glial health but harming neurons.

## Key findings

- m6A levels increase with age and disease in the Drosophila brain, affecting key neuronal transcripts.
- Mettl3 knockdown in neurons reduces longevity and increases DNA damage, while in glia it reduces tau pathology and increases survival.
- Mettl3 has a beneficial role in neurons but a harmful role in glia under chronic stress conditions.

## Abstract

The aging brain is highly vulnerable to cellular stress, and neurons employ numerous mechanisms to combat neurotoxic proteins and promote healthy brain aging. The RNA modification m6A is highly enriched in the Drosophila brain and is critical for the acute heat stress response of the brain. Here we examine m6A in the fly brain with the chronic stresses of aging and degenerative disease. m6A levels dynamically increased with both age and disease in the brain, marking integral neuronal identity and signaling pathway transcripts that decline in level with age and disease. Unexpectedly, there is opposing impact of m6A transcripts in neurons versus glia, which conferred different outcomes on animal health span upon Mettl3 knockdown to reduce m6A: whereas Mettl3 function is normally beneficial to neurons, it is deleterious to glia. Moreover, knockdown of Mettl3 in glial tauopathy reduced tau pathology and increased animal survival. These findings provide mechanistic insight into regulation of m6A modified transcripts with age and disease, highlighting an overall beneficial function of Mettl3 in neurons in response to chronic stresses, versus a deleterious impact in glia.

m6A levels increase with age in the brain and in the brains of animals expressing human Aβ42 in neurons. Knockdown of Mettl3 in neurons decreases longevity and but increases translation efficiency by TRAP assay, and increases DNA damage. Knockdown of Mettl3 in glial cells increases longevity and decreases translation efficiency of m6A modified transcripts.