The<i>MAPT</i>gene is differentially methylated in the progressive supranuclear palsy brain

Huin, Vincent; Deramecourt, Vincent; Caparros-Lefebvre, D.; Maurage, Claude‐Alain; Duyckaerts, Charles; Kovari, Eniko Veronika; Pasquier, Florence; Buée‐Scherrer, Valérie; Labreuche, Julien; Behal, Hélène; Buée, Luc; Dhaenens, Claire‐Marie; Sablonnière, Bernard

doi:10.1002/mds.26820

Cited by 28 publications

(21 citation statements)

References 40 publications

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“…a sequence missing from our construct) might potentiate MAPT ’s activity in vivo . Indeed, we recently characterized a regulatory region in intron 0 (upstream of a short CpG island and containing a CpG site that is hypomethylated in patients with PSP 13 ), located 13kb upstream of exon 1. We suspect that this site influences MAPT expression, as has already been described for other elements (such as SNPs and long, non-coding RNAs) in intron 0 19 – 22 .…”

Section: Discussionmentioning

confidence: 99%

“…The present study included brain tissue samples from 35 patients (22 with AD and 13 with PSP) and 18 non-clinical controls. Most of these cases have been described previously 13 .…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

“…The existence of an additional promoter has been suggested by Andreadis 11 , with a view to explaining tissue-specific differences in MAPT mRNA profiles and the MAPT gene’s transcriptional response to transcription and growth factors. Interestingly, our study of tissue from the frontal cortex of patients with progressive supranuclear palsy (PSP) previously highlighted significant hypomethylation of a CpG site located in the CpG island shore 13kb upstream of E1 13 . This region contains several putative regulatory features, such as a CpG island, DNase I clusters, binding sites for the transcription factor CCCTC-binding factor, and the histone mark H3K27Ac.…”

Section: Introductionmentioning

confidence: 99%

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Alternative promoter usage generates novel shorter MAPT mRNA transcripts in Alzheimer’s disease and progressive supranuclear palsy brains

Huin

Buée

Behal

et al. 2017

Sci Rep

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Alternative promoter usage is an important mechanism for transcriptome diversity and the regulation of gene expression. Indeed, this alternative usage may influence tissue/subcellular specificity, protein translation and function of the proteins. The existence of an alternative promoter for MAPT gene was considered for a long time to explain differential tissue specificity and differential response to transcription and growth factors between mRNA transcripts. The alternative promoter usage could explain partly the different tau proteins expression patterns observed in tauopathies. Here, we report on our discovery of a functional alternative promoter for MAPT, located upstream of the gene’s second exon (exon 1). By analyzing genome databases and brain tissue from control individuals and patients with Alzheimer’s disease or progressive supranuclear palsy, we identified novel shorter transcripts derived from this alternative promoter. These transcripts are increased in patients’ brain tissue as assessed by 5′RACE-PCR and qPCR. We suggest that these new MAPT isoforms can be translated into normal or amino-terminal-truncated tau proteins. We further suggest that activation of MAPT’s alternative promoter under pathological conditions leads to the production of truncated proteins, changes in protein localization and function, and thus neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

“…The present study included brain tissue samples from 35 patients (22 with AD and 13 with PSP) and 18 non-clinical controls. Most of these cases have been described previously 13 .…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alternative promoter usage generates novel shorter MAPT mRNA transcripts in Alzheimer’s disease and progressive supranuclear palsy brains

Huin

Buée

Behal

et al. 2017

Sci Rep

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“…[14][15][16][17]31,32 Our monozygotic twin pair with juvenile PD or PD with IST-naïve patients showed the intrinsic demethylation of ADORA2A those were chronologically restored after the IST treatment. Concerning about the DNA demethylation, which are small differences in NC (<5%) and in aging process (<10%), 33,34 biomarker of PD. 35 Regenerative medicine will play an essential role in the treatment of PD in the near future.…”

Section: Discussionmentioning

confidence: 99%

“…Human Jurkat genomic DNA was compared as standards. #, large demethylation differences (>10%) 33,34 ( Figure 3B). After 12 months of the IST treatment, A 2A R-m expression levels appeared to be decreased in samples obtained from MI or SI responsiveness except for AW, suggesting positive test may be associated to CGI-I effectiveness.…”

Section: Changes In Blood Biomarkersmentioning

confidence: 99%

Parkinson's disease therapy with Istradefylline and blood biomarkers of epigenetics

Kanzato¹,

Nakachi²,

Naka³

et al. 2020

Neurology & Clinical Neurosc

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Background Istradefylline (IST), an adenosine A2A receptor antagonist, has been used since 2013 in Japan as an adjunctive therapy to levodopa (L‐DOPA) for patients with Parkinson's disease (PD). The long‐term use of IST as an adjunct to L‐DOPA (IST‐LD) was herein investigated to clarify the cooperative potential to keep motor functions, and an epigenetic modification for disease‐specific up‐regulated A2AR signals. Methods The cohort comprising 62 PD patients with diurnal variations in motor function were treated with IST‐LD for 36 months, and clinical and biomarker parameters were evaluated. One monozygotic twin pair with juvenile PD and eight healthy control (HC) subjects were recruited for analyses of epigenetic biomarkers with peripheral blood lymphocyte (PBL): the A2AR protein (A2AR‐p), A2AR mRNA (A2AR‐m), and DNA methylation of the ADORA2A (Chr22q11.23) and DRD1 (Chr5q35.1) genes. Results IST‐LD partially reversed locomotive dysfunction and motor off time and did not promote the severe dyskinesia (LID) develop. A2AR expression levels of the PBL were higher in IST‐naïve PD patients than in HC, which were associated with the effectiveness of IST‐LD and clinical global impression improvements. Intrinsic DNA demethylation of the ADORA2A gene were observed in juvenile monozygotic twin pair of the PD and IST‐naïve PD patients, which were reversed by IST‐LD at 12 months. Conclusions IST‐LD was cooperative for long term to preserve motor execution controls and global daily activities improvement, through the canonical pharmacodynamics of inhibiting A2AR signaling, and also via the epigenetic modification on the ADORA2A gene.

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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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TheMAPTgene is differentially methylated in the progressive supranuclear palsy brain

Cited by 28 publications

References 40 publications

Alternative promoter usage generates novel shorter MAPT mRNA transcripts in Alzheimer’s disease and progressive supranuclear palsy brains

Alternative promoter usage generates novel shorter MAPT mRNA transcripts in Alzheimer’s disease and progressive supranuclear palsy brains

Parkinson's disease therapy with Istradefylline and blood biomarkers of epigenetics

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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