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

A Morales; E Korsakova; N Mansooralavi; A Ravikumar; G Rivas; P Soliman; L Rodriguez; T McDaniel; A Lund; B Cooper; A Bhaduri; W E Lowry

doi:10.1016/j.stemcr.2025.102645

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

Stem Cell Reports. 2025 Oct 14;20(10):102645. doi: 10.1016/j.stemcr.2025.102645. Epub 2025 Sep 25.

Authors

A Morales¹, E Korsakova², N Mansooralavi³, A Ravikumar⁴, G Rivas⁴, P Soliman⁵, L Rodriguez⁵, T McDaniel⁴, A Lund⁴, B Cooper⁴, A Bhaduri⁶, W E Lowry⁷

Affiliations

¹ Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
² Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
³ Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA.
⁴ Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
⁵ Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA.
⁶ Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Department of Biological Chemistry, DGSOM, UCLA, Los Angeles, CA 90095, USA.
⁷ Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA; Division of Dermatology, DGSOM, UCLA, Los Angeles, CA 90095, USA; Broad Center for Regenerative Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: blowry@ucla.edu.

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.

Keywords: CDKL5; DNA repair; MECP2; PARP1; Rett syndrome; human neurons; intellectual disability; senescence.

MeSH terms

Animals
Cellular Senescence / genetics
DNA Damage*
DNA Repair
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Methyl-CpG-Binding Protein 2* / genetics
Methyl-CpG-Binding Protein 2* / metabolism
Neurons* / metabolism
Neurons* / pathology
Poly (ADP-Ribose) Polymerase-1* / genetics
Poly (ADP-Ribose) Polymerase-1* / metabolism
Protein Binding
Rett Syndrome* / genetics
Rett Syndrome* / metabolism
Rett Syndrome* / pathology

Substances

Methyl-CpG-Binding Protein 2
Poly (ADP-Ribose) Polymerase-1
PARP1 protein, human
MECP2 protein, human