Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies

Paolo Reho; Sara Saez-Atienzar; Paola Ruffo; Sultana Solaiman; Zalak Shah; Ruth Chia; Karri Kaivola; Bryan J Traynor; Bension S Tilley; Steve M Gentleman; Angela K Hodges; Dag Aarsland; Edwin S Monuki; Kathy L Newell; Randy Woltjer; Marilyn S Albert; Ted M Dawson; Liana S Rosenthal; Juan C Troncoso; Olga Pletnikova; Geidy E Serrano; Thomas G Beach; Hariharan P Easwaran; Sonja W Scholz

doi:10.1038/s42003-023-05725-x

Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies

Commun Biol. 2024 Jan 5;7(1):35. doi: 10.1038/s42003-023-05725-x.

Authors

Paolo Reho^{1

2}, Sara Saez-Atienzar³, Paola Ruffo^{3

4}, Sultana Solaiman¹, Zalak Shah¹, Ruth Chia³, Karri Kaivola¹, Bryan J Traynor³, Bension S Tilley⁵, Steve M Gentleman⁵, Angela K Hodges⁶, Dag Aarsland^{6

7}, Edwin S Monuki⁸, Kathy L Newell⁹, Randy Woltjer¹⁰, Marilyn S Albert¹¹, Ted M Dawson^{11

12

13

14}, Liana S Rosenthal¹¹, Juan C Troncoso¹⁵, Olga Pletnikova¹⁶, Geidy E Serrano¹⁷, Thomas G Beach¹⁷, Hariharan P Easwaran¹⁸, Sonja W Scholz^{19

20}

Affiliations

¹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
² Laboratory of Precision Environmental Health, Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
³ Neuromuscular Diseases Research Section, National Institute on Aging, Bethesda, MD, USA.
⁴ Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
⁵ Neuropathology Unit, Department of Brain Sciences, Imperial College London, London, UK.
⁶ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁷ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁸ Department of Pathology & Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA, USA.
⁹ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Department of Neurology, Oregon Health & Sciences University, Portland, OR, USA.
¹¹ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹² Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA.
¹⁶ Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
¹⁷ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
¹⁸ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
¹⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA. sonja.scholz@nih.gov.
²⁰ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. sonja.scholz@nih.gov.

Abstract

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aged
Cerebellum
DNA Methylation
Epigenome
Humans
Lewy Bodies / genetics
Lewy Body Disease* / genetics

Abstract

Publication types

MeSH terms

Grants and funding