- September 2, 2025
- Victor Faundez, et al., Emory University
Topic/Product:
CNS Disease Panel 120
Disease Area:
Rett syndrome
Sample Type:
CSF
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. Like other genetic neurodevelopmental disorders, it lacks molecular biomarkers to evaluate disease and therapeutic outcomes. We present a strategy to define biomarkers of MeCP2 dysfunction in brain with potential to delineate mechanisms and monitor therapeutic interventions. This strategy relies on a library of proteins responsive to Mecp2 gene dosage and correlated with molecular and clinical outcomes after AAV9-mediated MECP2 gene therapy in Mecp2-KO mice. Gene rescue restored MeCP2 in brain, improved clinical phenotypes, and reverted transcriptome and proteome abnormalities. We identified 327 shared proteins among 1852 cortical and hippocampal proteins responsive to Mecp2/MECP2. Of these, 119 also displayed Mecp2/MECP2-dependent transcript changes. Both the Mecp2-responsive proteome and transcript–protein pairs were enriched in synaptic and metabolic pathways, including central carbon and NAD+ metabolism. We used this therapy-responsive protein library to guide selection of candidate cerebrospinal fluid (CSF) biomarkers in RTT. CSF composition from neurotypical and RTT groups was analyzed using ultrasensitive nucleic acid-based multiplexed ELISA. Twenty-eight proteins were altered in RTT, nine overlapping with Mecp2 dosage- and therapy-sensitive proteins. Multivariate regression linked several candidates to Mecp2/MeCP2 abundance and phenotypic improvement in mice. This paradigm provides a rigorous molecular systems-level framework integrating genetics, preclinical gene therapy, and clinical metrics to define robust cross-species biomarkers and mechanisms in RTT, with potential applicability to other neurodevelopmental disorders.
Authors & Affiliations
Stephanie Zla c†1, Eric Dammer†2, Amanda Crocker†3, Duc Duong†2, Jim Selfridge4, Kamal KE Gadalla4,12, Avan Gokhale1, Brendan R. Tobin5, Levi B. Wood6, Mar na Zandl-Lang7, Lucia Abela8, Barbara Plecko7, Anupam Patgiri9, Walter E. Kaufmann10, Randall Carpenter11, Stuart Cobb4, Victor Faundez1
- Department of Cell Biology, Emory University, Atlanta, Georgia, USA, 30322
- Department of Biochemistry, Emory University, Atlanta, Georgia, USA, 30322
- Program in Neuroscience, Middlebury College, Middlebury, Vermont 05753.
- Simons Ini a ve for the Developing Brain, Ins tute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, EH8 9XD, UK.
- School of Chemical and Biomolecular Engineering, Georgia Ins tute of Technology, 315 Ferst Dr., Atlanta, GA 30332
- George W. Woodruff School of Mechanical Engineering, Georgia Ins tute of Technology and Parker H. Pet Instute for Bioengineering, Atlanta, GA 30332
- Department of Paediatrics and Adolescent Medicine, Division of General Paediatrics, University Childrens’ Hospital Graz, Medical University of Graz, 8036 Graz, Austria
- University Children’s Hospital Zurich – Eleonore Foundation, Lenggstrasse 30 8008 Zurich, Switzerland.
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia, USA, 30322
- Department of Human Gene cs, Emory University, Atlanta, Georgia, USA, 30322 and Department of Neurology, Boston Children’s Hospital, Boston, Massachuse s, USA, 02115
- Re Syndrome Research Trust, Trumbull, CT 06611, USA
- Current address: Department of Biosciences, No ngham Trent University, No ngham, NG11 8NS, UK