# Probing DNA damage in Rett syndrome neurons uncovers a role for MECP2 regulation of PARP1

## TL;DR

This study shows that DNA damage in neurons lacking MECP2, a protein linked to Rett syndrome, causes dysfunction, and restoring PARP1 activity can reverse these effects.

## Contribution

The study reveals MECP2 regulates PARP1 activity, and restoring PARP1 can reverse DNA damage and dysfunction in Rett syndrome neurons.

## Key findings

- MECP2 interacts with PARP1 and regulates its activity in neurons.
- Restoring PARP1 activity in MECP2-null neurons reverses DNA damage and dysfunction.
- CDKL5-null neurons also show DNA damage and senescence similar to Rett syndrome neurons.

## Abstract

Methyl-CpG-binding protein 2 (MECP2)/Rett syndrome is characterized by a postnatal loss of neurophysiological function and regression of childhood development. While Rett neurons have been described as showing elevated senescence and P53 activity, here we show that molecular and physiological dysfunction in neurons lacking MECP2 is triggered by elevated DNA damage. Using human induced pluripotent stem cell (hiPSC)-derived isogenic lines, we find that MECP2 directly interacts with members of the DNA repair machinery, including PARP1. Here, we present evidence that MECP2 also regulates PARP1 activity, and restoration of PARP1 activity in MECP2-null neurons can reverse DNA damage, senescence, dendritic branching defects, and metabolic dysfunction. These data from a human disease-in-a-dish model system support the notion that dysfunction in Rett syndrome neurons could be caused by changes in PARP activity.

•DNA damage in MECP2-null neurons is a primary trigger for senescence•CDKL5-null neurons also show DNA damage and senescence, similar to Rett syndrome neurons•MECP2 interacts with PARP1 and regulates its activity•Restoration of PARP1 activity in MECP2-null neurons reverses dysfunction

DNA damage in MECP2-null neurons is a primary trigger for senescence

CDKL5-null neurons also show DNA damage and senescence, similar to Rett syndrome neurons

MECP2 interacts with PARP1 and regulates its activity

Restoration of PARP1 activity in MECP2-null neurons reverses dysfunction

Here, we show that MECP2 interacts with PARP1 to regulate its activity, and this interaction appears to be critical for phenotypes in neurons lacking MECP2 function, as in Rett syndrome. Inhibiting PARP1 function mimics aspects of loss of MECP2, and restoring PARP1 activity in MECP2-null neurons improves their physiology.