Epigenetic Modifications in Alzheimer’s Neuropathology and Therapeutics

Esposito, Michelle; Sherr, Goldie Libby

doi:10.3389/fnins.2019.00476

Cited by 61 publications

(48 citation statements)

References 126 publications

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“…Results reported by Dr. Cahill at the symposium have since been published (Thejer, Adhikary, Kaur, et al, 2020;Thejer, Adhikary, Teakel, et al, 2020). Perturbations in glucose metabolism, epigenetics and mitochondria are all symptoms of AD (Cenini and Voos, 2019;Ehrlich, 2019;Esposito and Sherr, 2019). Notably, gastrulation establishes the platform upon which subsequent epigenetic determination of animal tissue-specific differentiated cell identity is based, and this may be related to changes in PGRMC1 function regulated by phosphorylation.…”

Section: The Role Of the S2r Complex Protein Pgrmc1 In Health And Patmentioning

confidence: 99%

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Izzo

Colom‐Cadena

Riad

et al. 2020

eNeuro

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The sigma-2 receptor (S2R) complex has been implicated in central nervous system disorders ranging from anxiety and depression to neurodegenerative disorders such as Alzheimer's disease (AD). The proteins comprising the S2R complex impact processes including autophagy, cholesterol synthesis, progesterone signaling, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. While there has been much progress in understanding the role of S2R in cellular processes and its potential therapeutic value, a great deal remains unknown. The International Symposium on Sigma-2 Receptors is held in conjunction with the annual Society for Neuroscience conference in order to promote collaboration and advance the field of S2R research. This review summarizes updates presented at the Fourth International Symposium on Sigma-2 Receptors: Role in Health and Disease, a Satellite Symposium held at the 2019 Society for Neuroscience (SfN) conference. Interdisciplinary members of the S2R research community presented both previously published and preliminary results from ongoing studies of the role of S2R in cellular metabolism, the anatomical and cellular expression patterns of S2R, the relationship between S2R and amyloid beta in AD, the role of S2R complex protein PGRMC1 in health and disease, and the efforts to design new S2R ligands for the purposes of research and drug development. The proceedings from this symposium are reported here as an update on the field of S2R research, as well as to highlight the value of the symposia that occur yearly in conjunction with the SfN conference.

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Section: The Role Of the S2r Complex Protein Pgrmc1 In Health And Patmentioning

confidence: 99%

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Izzo

Colom‐Cadena

Riad

et al. 2020

eNeuro

View full text Add to dashboard Cite

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“…These patterns of synchronization ultimately guide developmental pathways during embryogenesis. Although aberrations in posttranslational modifications are often associated with developmental diseases including tumorigenesis [ 4 , 5 , 6 , 7 , 8 ], posttranslational events can also be manipulated and/or targeted for positive clinical applications [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells

Gordon

Reynolds

Brown

2020

Veterinary Sciences

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Neuroblastoma, the most common extracranial solid tumor in children, accounts for 15% of all pediatric cancer deaths. Pharmaceutical applications of S-Nitrosylation, which, under normal conditions is involved with a host of epigenetic and embryological development pathways, have exhibited great potential for use as adjuvant therapeutics in the clinical management of cancer. Herein, an evaluation of the impact of nitric oxide (NO) as a potent anticancer agent on murine neuroblastoma cells is presented. Excitingly cell viability, colony formation, and non-carcinogenic cell analysis illustrate the significance and practicality of NO as a cytotoxic anticancer therapeutic. Resazurin, WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt), and MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphyltetrazolium bromide) assays consistently displayed a moderate,~20-25% reduction in cell viability after exposure to 1 mM S-Nitrosoglutathione (GSNO). A colony formation assay demonstrated that treated cells no longer exhibited colony formation capacity. Identically GSNO-treated Adult Human Dermal Fibroblasts (HDFa) exhibited no decrease in viability, indicating potential discrimination between neoplastic and normal cells. Collectively, our findings indicate a potential application for NO as an adjuvant therapeutic in the clinical management of neuroblastoma. Vet. Sci. 2020, 7, 51 2 of 15 and intricacy of disease progression and response to treatment, the International Neuroblastoma Staging System (INSS) was developed to classify the extent of the disease and impact the treatment approach [13]. Three distinct stages comprise the INSS: low, intermediate, and high risk. Each risk group is comprised of definitions containing the stage(s), patient age, presence/absence of the MYCN gene, histology, and DNA ploidy. Currently, low risk tumors represent ≤25% of initial diagnoses, intermediate risk represent about~15% of initial diagnoses, and high risk tumors are the most commonly diagnosed, at ≥60% [11]. In patients with low risk disease, surgery and observation are the central therapeutic options that contribute to >90% survival [14,15]. Patients with intermediate risk disease typically receive a variety of sequential treatments including chemotherapy, surgery, and radiation therapy, if necessary. Survival rates in this group drop some but remain favorable at >80% [16,17]. High risk treatment protocols commence in an identical manner and additional treatments are frequently required, such as immunotherapy and bone marrow transplant. Despite the advances in treatments for low and intermediate risk disease, patients with high risk disease continue to face particularly poor prognosis, with~40% five-year overall survival rates [18,19]. Overall relapse rates are additionally overwhelming, at >60% [12]. In a similar fashion, treatments for recurrent low-risk and intermediate-risk disease are largely effective. However, recurrent high-risk neuroblastoma remains a significant challenge. Due to the a...

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“…Among the epigenetic alterations found in AD, DNA methylation and histone modifications show evident deregulation. It has been demonstrated that in AD brains changes in DNA methylation affect to a few common gene loci which play an essential role in the formation of Aβ plaques (Lord and Cruchaga, 2014;Watson et al, 2016;Qazi et al, 2018;Armstrong et al, 2019;Esposito and Sherr, 2019;Prasad and Jho, 2019). Among them, of particular interest are the differences in methylation in different regions of the APP gene promoters in the brains of humans with AD and these changes have been associated with neuropathological markers of this disorder (Bradley-Whitman and Lovell, 2013).…”

Section: Dna Damage and Repairmentioning

confidence: 99%

“…Also, chromatin organizing proteins and epigenetic regulators are mislocated in AD, affecting chromatin architecture (Winick-Ng and Rylett, 2018). Finally, in AD, other epigenetic modifications such as alterations in chromatin remodelers, phosphorylation of histones have been found (Esposito and Sherr, 2019), and might be associated with senescence.…”

Section: Dna Damage and Repairmentioning

confidence: 99%

Cellular Senescence in Neurodegenerative Diseases

Martı́nez-Cué

Rueda

2020

Front. Cell. Neurosci.

191

132

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Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Although several factors can induce senescence, DNA damage, oxidative stress, neuroinflammation, and altered proteostasis have been shown to play a role in its onset. Oxidative stress contributes to accelerated aging and cognitive dysfunction stages affecting neurogenesis, neuronal differentiation, connectivity, and survival. During later life stages, it is implicated in the progression of cognitive decline, synapse loss, and neuronal degeneration. Also, neuroinflammation exacerbates oxidative stress, synaptic dysfunction, and neuronal death through the harmful effects of pro-inflammatory cytokines on cell proliferation and maturation. Both oxidative stress and neuroinflammation can induce DNA damage and alterations in DNA repair that, in turn, can exacerbate them. Another important feature associated with senescence is altered proteostasis. Because of the disruption in the function and balance of the proteome, senescence can modify the proper synthesis, folding, quality control, and degradation rate of proteins producing, in some diseases, misfolded proteins or aggregation of abnormal proteins. There is an extensive body of literature that associates cellular senescence with several neurodegenerative disorders including Alzheimer's disease (AD), Down syndrome (DS), and Parkinson's disease (PD). This review summarizes the evidence of the shared neuropathological events in these neurodegenerative diseases and the implication of cellular senescence in their onset or aggravation. Understanding the role that cellular senescence plays in them could help to develop new therapeutic strategies.

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Epigenetic Modifications in Alzheimer’s Neuropathology and Therapeutics

Cited by 61 publications

References 126 publications

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells

Cellular Senescence in Neurodegenerative Diseases

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