DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease

Sánchez-Mut, José Vicente; Aso, Ester; Panayotis, Nicolás; Lott, Ira T.; Dierssen, Mara; Rábano, Alberto; Urdinguio, Rocío G.; Fernández, Agustín F.; Astudillo, Aurora; Martín‐Subero, José I.; Bálint, Balázs; Fraga, Mario F.; Gómez, Antonio; Gurnot, Cécile; Roux, Jean‐Christophe; Ávila, Jesús; Hensch, Takao K.; Ferrer, Isidro; Esteller, Manel

doi:10.1093/brain/awt237

Cited by 120 publications

(79 citation statements)

References 73 publications

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“…Natural variation in sequestosome‐1, which escorts aggregates to autophagosomes, is associated with early‐onset AD (Cuyvers et al ., 2015). Spectrin has been utilized as a model of spontaneous amyloid formation (Castello et al ., 2015), and the spectrin β4 locus is one of three genes strongly hypermethylated in AD (Sanchez‐Mut et al ., 2013). Phosphorylation of synapsin‐1 triggers neurotransmitter release but is blocked by binding huntingtin protein in HD (Xu et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…Sanchez-Mut et al 60 studied DNA methylation in the brain using a microarray containing the 5′ regulatory region of 384 genes that are associated with neuroplasticity and with mental illness. In the frontal cortex of transgenic AD mice, they observed differential methylation in four genes compared with controls.…”

Section: Epigenetic Alterations In Ad Dna Methylationmentioning

confidence: 99%

Epigenetic mechanisms in Alzheimer's disease

Balázs¹

2014

DNND

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Abstract:The worldwide increase in life expectancy is leading to an increase in age-dependent diseases, including nonfamilial, sporadic Alzheimer's disease (AD), which is the subject of this review. The etiology and pathophysiology of the disease is not fully understood, but present observations suggest that, in addition to genetic risk factors, environmental influences may be involved via epigenetic mechanisms. Currently, there is no effective treatment, but there are indications that lifestyle has an impact on the development of the disease. This view is supported by preclinical studies not only showing that human lifestyle-equivalent interventions have a positive effect on cognitive function in animal models of AD, but also indicating the involvement of underlying epigenetic mechanisms. After a brief overview of the most characteristic chromatin modifications, ie, DNA methylation and histone modifications, epigenetic changes associated with aging are considered, given that aging is the most important risk factor for AD. This is followed by a description of some epigenetic alterations recognized in AD. The impact of environmental factors and lifestyle on the epigenome is then considered. Epigenetic treatments with HDAC inhibitors and RNA-based drugs are considered, which -while still in preclinical stages -are promising for potential benefit. It is concluded that while awaiting results from clinical trials in progress, focusing on lifestyle adjustments with an epigenetic background are the best way to prevent/delay the onset of this devastating disease.

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“…Finally, a recent study from our group has analyzed 12 distinct mouse brain regions according to their genome-wide DNA methylation patterns and characterized their unique epigenetic landscapes. Using these methylome DNA methylation-associated silencing of three targets genes has been identified: TBXA2R, SORBS3, and SPTBN4 (Sanchez-Mut et al 2013). More recently, using 27K platform DNA methylation profiles of human hippocampus from controls and AD patients, they have also identified the functional role of promoter hypermethylation silencing in AD of DUSP22 gene (Sanchez-Mut et al 2014).…”

Section: Neurodegenerative: Alzheimer's Diseasementioning

confidence: 99%

Epigenomic Biomarkers for the Advance of Personalized Medicine

Méndez‐González

Sandoval

2015

Translational Bioinformatics

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Epigenetic factors (DNA methylation, histone modifications, or ncRNAs) are involved in gene expression regulation. Thus, determining abnormal epigenetic changes is a suitable approach to extract meaningful information about human diseases. An altered pattern of epigenetic modifications has been firstly defined as a hallmark for cancer, although it is also a key element to many common human diseases, such as cardiovascular, metabolic, and neurological pathologies. During the last decade, the advent of genome-scale analysis techniques applied to epigenetics has provided a massive amount of data, enabling an important advance in the molecular mechanisms underlying disease initiation, progression, and expansion. Disease-specific epigenomic signatures, mainly based on DNA methylation analysis, have been studied for several clinical purposes including prognostics and diagnostics, as well as disease-specific chemotherapy response. Using noninvasive specimens, epigenetic profiling holds the promise of being of clinical value in the management of patients, even at the early stages of disease. Additionally, epigenetic marks have also been catalogued as targets for pharmacological drugs. The upgrade of epigenetic research to epigenomics together with other -omics would tackle the many unanswered questions in the field, paving the path to achieve a more precise personalized medicine.

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DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease

Cited by 120 publications

References 73 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Epigenetic mechanisms in Alzheimer's disease

Epigenomic Biomarkers for the Advance of Personalized Medicine

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DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease

Cited by 120 publications

References 73 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Epigenetic mechanisms in Alzheimer&#39;s disease

Epigenomic Biomarkers for the Advance of Personalized Medicine

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Epigenetic mechanisms in Alzheimer's disease