Journal Article

DZNE-2023-00758

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Epigenetic Age Acceleration in Frontotemporal Lobar Degeneration: A Comprehensive Analysis in the Blood and Brain.

Murthy, M. ; Rizzu, P.DZNE* ; Heutink, P.DZNE* ; Mill, J. ; Lashley, T. ; Bettencourt, C.

2023
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/cells12141922

Abstract: Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge, and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD.

Keyword(s): Humans (MeSH) ; Frontotemporal Dementia (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Brain (MeSH) ; Supranuclear Palsy, Progressive: genetics (MeSH) ; Mutation: genetics (MeSH) ; Ubiquitin-Specific Proteases (MeSH) ; DNA methylation aging ; epigenetic clock ; frontotemporal dementia ; frontotemporal lobar degeneration ; progressive supranuclear palsy ; OTUD4 protein, human ; Ubiquitin-Specific Proteases

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Contributing Institute(s):

1. Applied Genomics for Neurodegenerative Diseases (AG Rizzu)
2. Genome Biology of Neurodegenerative Diseases (AG Heutink)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2023

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