DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons from Alzheimer’s, Related Tauopathies and Genetic Tauopathies

Zimmer-Bensch, Geraldine; Zempel, Hans

doi:10.3390/cells10113064

Cited by 17 publications

(24 citation statements)

References 161 publications

(176 reference statements)

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“…As a result, DNMTs are degrade with DNA demethylation, and silent related tumor suppressor genes are restored to expression. 255 , 258 , 260 Recent studies have reviewed the antitumor effect of epigenetic drugs in various diseases. 255 , 257 , 259 , 261 , 262 , 263 And antitumor drugs also play an important role in treating chronic inflammation‐related diseases, including autoimmune disorders and ND.…”

Section: Epigenetic‐targeted Therapy For Inflammation‐related Diseasesmentioning

confidence: 99%

“…These nucleoside analogs inhibit DNA synthesis by binding to DNA during the S phase, forming irreversible complex with DNMTs during this phase. As a result, DNMTs are degrade with DNA demethylation, and silent related tumor suppressor genes are restored to expression 255,258,260 . Recent studies have reviewed the antitumor effect of epigenetic drugs in various diseases 255,257,259,261–263 .…”

Section: Epigenetic‐targeted Therapy For Inflammation‐related Diseasesmentioning

confidence: 99%

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Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Zhang

Meng

Zhou

et al. 2022

MedComm

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Emerging evidence indicates that resolution of inflammation is a critical and dynamic endogenous process for host tissues defending against external invasive pathogens or internal tissue injury. It has long been known that autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses, leading to excessive and uncontrol tissue inflammation. The dysregulation of epigenetic alterations including DNA methylation, posttranslational modifications to histone proteins, and noncoding RNA expression has been implicated in a host of inflammatory disorders and the immune system. The inflammatory response is considered as a critical trigger of epigenetic alterations that in turn intercede inflammatory actions. Thus, understanding the molecular mechanism that dictates the outcome of targeting epigenetic regulators for inflammatory disease is required for inflammation resolution. In this article, we elucidate the critical role of the nuclear factor‐κB signaling pathway, JAK/STAT signaling pathway, and the NLRP3 inflammasome in chronic inflammatory diseases. And we formulate the relationship between inflammation, coronavirus disease 2019, and human cancers. Additionally, we review the mechanism of epigenetic modifications involved in inflammation and innate immune cells. All that matters is that we propose and discuss the rejuvenation potential of interventions that target epigenetic regulators and regulatory mechanisms for chronic inflammation‐associated diseases to improve therapeutic outcomes.

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Section: Epigenetic‐targeted Therapy For Inflammation‐related Diseasesmentioning

confidence: 99%

Section: Epigenetic‐targeted Therapy For Inflammation‐related Diseasesmentioning

confidence: 99%

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Zhang

Meng

Zhou

et al. 2022

MedComm

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“…Both PIMT and DNA methyltransferases use SAM as a cofactor (i.e., methyl donor). The main mechanistic hypothesis regarding how altered one‐carbon metabolism promotes AD focuses on decreased DNA methylation due to insufficient SAM as a cofactor for DNA methylation enzymes 32 . However, decreased PIMT activity is also a predictable outcome of limited SAM.…”

Section: The Pimt Hypothesismentioning

confidence: 99%

“…The main mechanistic hypothesis regarding how altered one-carbon metabolism promotes AD focuses on decreased DNA methylation due to insufficient SAM as a cofactor for DNA methylation enzymes. 32 However, decreased PIMT activity is also a predictable outcome of limited SAM. Thus, the PIMT hypothesis (posited herein) and the DNA hypomethylation hypothesis are not only not mutually exclusive, they are biologically linked.…”

Section: The Pimt Hypothesismentioning

confidence: 99%

The role of PIMT in Alzheimer's disease pathogenesis: A novel hypothesis

D’Alessandro

Lukens

Zimring

2023

Alzheimer's & Dementia

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There are multiple theories of Alzheimer's disease pathogenesis. One major theory is that oxidation of amyloid beta (Aβ) promotes plaque deposition that directly contributes to pathology. A competing theory is that hypomethylation of DNA (due to altered one carbon metabolism) results in pathology through altered gene regulation. Herein, we propose a novel hypothesis involving L‐isoaspartyl methyltransferase (PIMT) that unifies the Aβ and DNA hypomethylation hypotheses into a single model. Importantly, the proposed model allows bidirectional regulation of Aβ oxidation and DNA hypomethylation. The proposed hypothesis does not exclude simultaneous contributions by other mechanisms (e.g., neurofibrillary tangles). The new hypothesis is formulated to encompass oxidative stress, fibrillation, DNA hypomethylation, and metabolic perturbations in one carbon metabolism (i.e., methionine and folate cycles). In addition, deductive predictions of the hypothesis are presented both to guide empirical testing of the hypothesis and to provide candidate strategies for therapeutic intervention and/or nutritional modification.HIGHLIGHTS PIMT repairs L‐isoaspartyl groups on amyloid beta and decreases fibrillation. SAM is a common methyl donor for PIMT and DNA methyltransferases. Increased PIMT activity competes with DNA methylation and vice versa. The PIMT hypothesis bridges a gap between plaque and DNA methylation hypotheses.

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“…No data was used for this manuscript Zempel, 2021). Note that the number of tauopathies is likely to rise, as we expect more rare neurogenetic diseases to be discovered or categorized as tauopathy in the near future.…”

Section: Data Availability Statementmentioning

confidence: 99%

Genetic and sporadic forms of tauopathies—TAU as a disease driver for the majority of patients but the minority of tauopathies

Zempel

2023

Cytoskeleton

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Ageing‐associated tauopathies like frontotemporal dementia (FTD), variants thereof (like progressive supranuclear palsy (PSP), pick diseases (PiD), corticobasal degeneration (CBD)), and of course the most prevalent form of dementia, Alzheimer Disease (AD), are widely recognized forms of tauopathies. The list of tauopathies is expanding. We now include: (i) tauopathies where the disease cause or trigger is clearly either physical, such as in Traumatic Brain Injury (TBI) or Chronic Traumatic Encephalopathy (CTE), and (ii) genetic diseases that result in tauopathy but have pathogenic genetic variants in genes not related to TAU. Examples of the latter are myotonic dystrophy Type 1 and Type 2 (DM1, DM2, due to pathogenic genetic variants in the genes DMPK and CNBP, respectively), Niemann–Pick Disease Type C (NPD, due to mutations in NPC1 or NPC2), Kufs Disease (CLN6), Christianson Syndrome (SLC9A6), familial forms of Parkinson Disease (PD), and many others. In terms of affected brain regions and cell types, intracellular distribution of TAU pathology/aggregates, age of disease onset, velocity of disease progression and spreading of TAU pathology, there is, however, little in common in most of these disease entities. Here, I reason that TAU/MAPT is causative for the minority of tauopathies (e.g., MAPT‐related FTD/PSP and Vacuolar Tauopathy (VCP)) and a critical mediator for others, like shown by overwhelming evidence for AD. However, TAU may also be a mere bystander or even protective in other settings. Improved understanding of rare tauopathies is necessary to develop specific treatments, but also to improve our understanding of the pathomechanistic role of TAU and to identify diseases that may profit from TAU‐based therapies.

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DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons from Alzheimer’s, Related Tauopathies and Genetic Tauopathies

Cited by 17 publications

References 161 publications

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy

The role of PIMT in Alzheimer's disease pathogenesis: A novel hypothesis

Genetic and sporadic forms of tauopathies—TAU as a disease driver for the majority of patients but the minority of tauopathies

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