Myotonic Dystrophy: an RNA Toxic Gain of Function Tauopathy?

Fernandez-Gomez, Francisco-José; Dhaenens, Claire‐Marie; Caillet-Boudin, Marie-Laure; Schraen‐Maschke, Susanna; Blum, David; Sablonnière, Bernard; Buée‐Scherrer, Valérie; Buée, Luc

doi:10.1007/978-981-32-9358-8_17

Cited by 12 publications

(13 citation statements)

References 96 publications

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“…Tau missplicing results in isoform‐specific impairment in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process 63 . In DM1, recent work has suggested an interplay between toxic RNA, disordered splicing, and the dysregulation of microtubule‐associated protein tau 64,65 . In DM1, the “foci,” consisting of accumulations of toxic RNA, are known sequester RNA‐binding proteins, such as splicing factors, consequently leading to dysregulated alternative splicing in neurons 64,65 .…”

Section: Discussionmentioning

confidence: 99%

Human brain pathology in myotonic dystrophy type 1: A systematic review

et al. 2021

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Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974–2017) and MEDLINE (index period 1887–2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full‐text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.

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Section: Discussionmentioning

confidence: 99%

Human brain pathology in myotonic dystrophy type 1: A systematic review

et al. 2021

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“…One of the better-described missplicing due to loss of MBNL2 is microtubule-associated protein tau ( MAPT ), as found in DM1 frontal cortex samples [ 82 ]. Abnormal expression of MAPT isoforms, excluding exons 2, 3 and 10, and progressive appearance of neurofibrillary tangles (NFTs) composed of intraneuronal aggregates of hyperphosphorylated tau protein, are present in DM1 patient samples, suggesting a tautopathy-like degeneration of brain tissue [ 83 , 84 ].…”

Section: Spliceopathy Due To Rna Toxicitymentioning

confidence: 99%

An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I

López-Martínez

Soblechero-Martín

Puente-Ovejero

et al. 2020

Genes

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Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3′ untranslated region (3′UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded transcripts, a decreased DMPK translation and the disruption of the chromatin structure, affecting neighboring genes expression. The muscleblind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) are two families of tissue-specific regulators of developmentally programmed alternative splicing that act as antagonist regulators of several pre-mRNA targets, including troponin 2 (TNNT2), insulin receptor (INSR), chloride channel 1 (CLCN1) and MBNL2. Sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology, inducing a spliceopathy that leads to a developmental remodelling of the transcriptome due to an adult-to-foetal splicing switch, which results in the loss of cell function and viability. Moreover, recent studies indicate that additional pathogenic mechanisms may also contribute to disease pathology, including a misregulation of cellular mRNA translation, localization and stability. This review focuses on the cause and effects of MBNL and CELF1 deregulation in DM1, describing the molecular mechanisms underlying alternative splicing misregulation for a deeper understanding of DM1 complexity. To contribute to this analysis, we have prepared a comprehensive list of transcript alterations involved in DM1 pathogenesis, as well as other deregulated mRNA processing pathways implications.

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“…Alternative splicing of Tau has also been reported postnatally in DM1. In a recent review, Fernandez-Gomez et al 26 noted that although Tau mRNA alternative splicing is generally firmly regulated, the somatic instability of the DM1 mutation causes a reversal of these splicing patterns such that fetal patterns of Tau are expressed in adult tissues. Additional studies have also shown that fetal forms of Tau were expressed in adult brain tissue in individuals with DM1, following the same pattern of misregulated expression as MBNL proteins.…”

Section: Discussionmentioning

confidence: 99%

DMPK mRNA Expression in Human Brain Tissue Throughout the Lifespan

et al. 2021

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ObjectiveMyotonic dystrophy is a multisystem disorder caused by a trinucleotide repeat expansion on the myotonic dystrophy protein kinase (DMPK) gene. To determine whether wildtype DMPK expression patterns vary as a function of age, we analyzed DMPK expression in the brain from 99 donors ranging from 5 postconceptional weeks to 80 years old.MethodsWe used the BrainSpan messenger RNA sequencing and the Yale Microarray data sets, which included brain tissue samples from 42 and 57 donors, respectively. Collectively, donors ranged in age from 5 postconceptional weeks to 80 years old. DMPK expression was normalized for each donor across regions available in both data sets. Restricted cubic spline linear regression models were used to analyze the effects of log-transformed age and sex on normalized DMPK expression data.ResultsAge was a statistically significant predictor of normalized DMPK expression pattern in the human brain in the BrainSpan (p < 0.005) and Yale data sets (p < 0.005). Sex was not a significant predictor. Across both data sets, normalized wildtype DMPK expression steadily increases during fetal development, peaks around birth, and then declines to reach a nadir around age 10.ConclusionsPeak expression of DMPK coincides with a time of dynamic brain development. Abnormal brain DMPK expression due to myotonic dystrophy may have implications for early brain development.

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Myotonic Dystrophy: an RNA Toxic Gain of Function Tauopathy?

Cited by 12 publications

References 96 publications

Human brain pathology in myotonic dystrophy type 1: A systematic review

Human brain pathology in myotonic dystrophy type 1: A systematic review

An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I

DMPK mRNA Expression in Human Brain Tissue Throughout the Lifespan

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