Altered splicing of Tau in DM1 is different from the foetal splicing process

AbstractAmong the different mechanisms underlying the etiopathogenesis of myotonic dystrophy type 1 (DM1), a backward reprogramming to a foetal splicing machinery is an interesting hypothesis. To address this possibility, Tau splicing, which is regulated during development and modified in DM1, was analyzed. Indeed, a preferential expression of the foetal Tau isoform, instead of the six normally found, is observed in adult DM1 brains. By using two cell lines, we show here that the cis-regulating elements necessary to generate the unique foetal Tau isoform are dispensable to reproduce the trans-dominant effect induced by DM1 mutation on Tau exon 2 inclusion. Our results suggest that the mis-splicing of Tau in DM1 is resulting from a disease-associated mechanism

ETR-3 represses Tau exons 2/3 inclusion, a splicing event abnormally enhanced in myotonic dystrophy type I

Altered splicing of transcripts, including the insulin receptor (IR) and the cardiac troponin (cTNT), is a key feature of myotonic dystrophy type I (DM1). CELF and MBNL splicing factor members regulate the splicing of those transcripts. We have previously described an alteration of Tau exon 2 splicing in DM1 brain, resulting in the favored exclusion of exon 2. However, the factors required for alternative splicing of Tau exon 2 remain undetermined. Here we report a decreased expression of CELF family member and MBNL transcripts in DM1 brains as assessed by RT-PCR. By using cellular models with a control- or DM1-like splicing pattern of Tau transcripts, we demonstrate that ETR-3 promotes selectively the exclusion of Tau exon 2. These results together with the analysis of Tau exon 6 and IR exon 11 splicing in brain, muscle, and cell models suggest that DM1 splicing alteration of several transcripts involves various factors

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers

International audienceINTRODUCTION:Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ42 and Aβ40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers.METHODS:One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included.RESULTS:Plasma Aβ1-42 and Aβ1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aβ1-42 and P = .04 for Aβ1-40). Globally, plasma Aβ1-42 correlated with age, Mini-Mental State Examination, and APOE ε4 allele. Plasma Aβ1-42 correlated with all CSF biomarkers in MCI but only with CSF Aβ42 in AD.DISCUSSION:Plasma Aβ was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers

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