DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons From Alzheimers, Related Tauopathies and Genetic Tauopathies

Zimmer-Bensch, Geraldine; Zempel, Hans

doi:10.20944/preprints202105.0717.v1

Cited by 3 publications

(1 citation statement)

References 109 publications

(122 reference statements)

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“…Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Pick's Disease (PiD), Argyrophilic Grain Disease (AGD) (Park et al, 2016). Here, we subdivide major tauopathies into either genetic diseases, in which proven inherited genetic mutations are the cause of the disease, or sporadic or idiopathic diseases, in which clear genetic causes are absent (Table 1) (For a more extensive list see Zimmer-Bensch and Zempel, 2021), and outline potential AAV-based gene therapy approaches.…”

Section: Introductionmentioning

confidence: 99%

AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

KABBANI¹,

Wunderlich²,

K鯤LER³

et al. 2022

Biocell

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Tauopathies comprise a spectrum of genetic and sporadic neurodegenerative diseases mainly characterized by the presence of hyperphosphorylated TAU protein aggregations in neurons or glia. Gene therapy, in particular adeno-associated virus (AAV)-based, is an effective medical approach for difficult-to-treat genetic diseases for which there are no convincing traditional therapies, such as tauopathies. Employing AAV-based gene therapy to treat, in particular, genetic tauopathies has many potential therapeutic benefits, but also drawbacks which need to be addressed in order to successfully and efficiently adapt this still unconventional therapy for the various types of tauopathies. In this Viewpoint, we briefly introduce some potentially treatable tauopathies, classify them according to their etiology, and discuss the potential advantages and possible problems of AAV-based gene therapy. Finally, we outline a future vision for the application of this promising therapeutic approach for genetic and sporadic tauopathies.

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Section: Introductionmentioning

confidence: 99%

AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

KABBANI¹,

Wunderlich²,

K鯤LER³

et al. 2022

Biocell

Self Cite

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Perinatal S-Adenosylmethionine Supplementation Represses PSEN1 Expression by the Cellular Epigenetic Memory of CpG and Non-CpG Methylation in Adult TgCRD8 Mice

Raia

Armeli

Cavallaro

et al. 2023

IJMS

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DNA methylation, the main epigenetic modification regulating gene expression, plays a role in the pathophysiology of neurodegeneration. Previous evidence indicates that 5′-flanking hypomethylation of PSEN1, a gene involved in the amyloidogenic pathway in Alzheimer’s disease (AD), boosts the AD-like phenotype in transgenic TgCRND8 mice. Supplementation with S-adenosylmethionine (SAM), the methyl donor in the DNA methylation reactions, reverts the pathological phenotype. Several studies indicate that epigenetic signatures, driving the shift between normal and diseased aging, can be acquired during the first stages of life, even in utero, and manifest phenotypically later on in life. Therefore, we decided to test whether SAM supplementation during the perinatal period (i.e., supplementing the mothers from mating to weaning) could exert a protective role towards AD-like symptom manifestation. We therefore compared the effect of post-weaning vs. perinatal SAM treatment in TgCRND8 mice by assessing PSEN1 methylation and expression and the development of amyloid plaques. We found that short-term perinatal supplementation was as effective as the longer post-weaning supplementation in repressing PSEN1 expression and amyloid deposition in adult mice. These results highlight the importance of epigenetic memory and methyl donor availability during early life to promote healthy aging and stress the functional role of non-CpG methylation.

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Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines

Ramos-Campoy,

Comas-Albertí,

Hervás

et al. 2024

IJMS

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Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue.

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DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons From Alzheimers, Related Tauopathies and Genetic Tauopathies

Cited by 3 publications

References 109 publications

AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

Perinatal S-Adenosylmethionine Supplementation Represses PSEN1 Expression by the Cellular Epigenetic Memory of CpG and Non-CpG Methylation in Adult TgCRD8 Mice

Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines

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