Altered Behavioral Responses Show GABA Sensitivity in Muscleblind-Like 2-Deficient Mice: Implications for CNS Symptoms in Myotonic Dystrophy

Edokpolor, Kamyra; Banerjee, Anwesha; McEachin, Zachary T.; Gu, Jingsheng; Kosti, Adam; Arboleda, J. D.; García, Paul S.; Wang, Eric T.; Bassell, Gary J.

doi:10.1523/eneuro.0218-22.2022

Cited by 3 publications

(2 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Knockout of the MBNL2 gene in mouse models has been associated with diabetes-related characteristics in the central nervous system, including abnormal rapid eye movement sleep tendencies and spatial memory deficits. Furthermore, these mice exhibited delayed recovery and prolonged sleep duration following general anesthesia when compared to wild-type mice ( 56 ). PIK3AP1 plays a crucial role in diverse inflammatory responses and the regulation of signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Elucidating sleep disorders: a comprehensive bioinformatics analysis of functional gene sets and hub genes

Lin,

Liu,

2024

Front. Immunol.

View full text Add to dashboard Cite

BackgroundSleep disorders (SD) are known to have a profound impact on human health and quality of life although their exact pathogenic mechanisms remain poorly understood. MethodsThe study first accessed SD datasets from the GEO and identified DEGs. These DEGs were then subjected to gene set enrichment analysis. Several advanced techniques, including the RF, SVM-RFE, PPI networks, and LASSO methodologies, were utilized to identify hub genes closely associated with SD. Additionally, the ssGSEA approach was employed to analyze immune cell infiltration and functional gene set scores in SD. DEGs were also scrutinized in relation to miRNA, and the DGIdb database was used to explore potential pharmacological treatments for SD. Furthermore, in an SD murine model, the expression levels of these hub genes were confirmed through RT-qPCR and Western Blot analyses.ResultsThe findings of the study indicate that DEGs are significantly enriched in functions and pathways related to immune cell activity, stress response, and neural system regulation. The analysis of immunoinfiltration demonstrated a marked elevation in the levels of Activated CD4+ T cells and CD8+ T cells in the SD cohort, accompanied by a notable rise in Central memory CD4 T cells, Central memory CD8 T cells, and Natural killer T cells. Using machine learning algorithms, the study also identified hub genes closely associated with SD, including IPO9, RAP2A, DDX17, MBNL2, PIK3AP1, and ZNF385A. Based on these genes, an SD diagnostic model was constructed and its efficacy validated across multiple datasets. In the SD murine model, the mRNA and protein expressions of these 6 hub genes were found to be consistent with the results of the bioinformatics analysis.ConclusionIn conclusion, this study identified 6 genes closely linked to SD, which may play pivotal roles in neural system development, the immune microenvironment, and inflammatory responses. Additionally, the key gene-based SD diagnostic model constructed in this study, validated on multiple datasets showed a high degree of reliability and accuracy, predicting its wide potential for clinical applications. However, limited by the range of data sources and sample size, this may affect the generalizability of the results.

show abstract

Section: Discussionmentioning

confidence: 99%

Elucidating sleep disorders: a comprehensive bioinformatics analysis of functional gene sets and hub genes

Lin,

Liu,

2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…In addition, deficits in motor coordination due to cerebellar glial and neuronal abnormalities caused by glutamate abnormal levels have been also described in DMSXL mice (Sicot et al, 2017). Finally, cognitive and REM sleep disorders as well as increased time of immobility in the absence of neuromuscular or locomotor deficits have been found in DM1 linked Mbnl2 knock-out mice (Charizanis et al, 2012;Edokpolor et al, 2022). Our study is the first to describe a sleeprelated phenotype in DMSXL mice as a relevant mouse model of early-onset forms of DM1.…”

Section: Discussionmentioning

confidence: 99%

Excessive rest time during active phase is reliably detected in a mouse model of myotonic dystrophy type 1 using home cage monitoring

Golini

Rigamonti²,

Raspa

et al. 2023

Front. Behav. Neurosci.

View full text Add to dashboard Cite

Myotonic dystrophy type 1 (DM1) is a dominantly inherited neuromuscular disease caused by the abnormal expansion of CTG-repeats in the 3′-untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene, characterized by multisystemic symptoms including muscle weakness, myotonia, cardio-respiratory problems, hypersomnia, cognitive dysfunction and behavioral abnormalities. Sleep-related disturbances are among the most reported symptoms that negatively affect the quality of life of patients and that are present in early and adult-onset forms of the disease. DMSXL mice carry a mutated human DMPK transgene containing >1,000 CTGrepeats, modeling an early onset, severe form of DM1. They exhibit a pathologic neuromuscular phenotype and also synaptic dysfunction resulting in neurological and behavioral deficits similar to those observed in patients. Additionally, they are underweight with a very high mortality within the first month after birth presenting several welfare issues. To specifically explore sleep/rest-related behaviors of this frail DM1 mouse model we used an automated home cage-based system that allows 24/7 monitoring of their activity non-invasively. We tested male and female DMSXL mice and their wild-type (WT) littermates in Digital Ventilated Cages (DVCR) assessing activity and rest parameters on day and night for 5 weeks. We demonstrated that DMSXL mice show reduced activity and regularity disruption index (RDI), higher percentage of zero activity per each hour and longer periods of rest during the active phase compared to WT. This novel rest-related phenotype in DMSXL mice, assessed unobtrusively, could be valuable to further explore mechanisms and potential therapeutic interventions to alleviate the very common symptom of excessive daytime sleepiness in DM1 patients.

show abstract

Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1

Nutter

Kidd

Carter

et al. 2023

Brain

View full text Add to dashboard Cite

Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knockin model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knockin mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from donors without neurologically unaffected (two females, three males; ages 50-70) and myotonic dystrophy type 1 donors (one female, three males; ages 50-70). To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55) and non-myotonic dystrophy patients (three females, four males; ages 26-51) and Western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knockin mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knockin mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output, and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.

show abstract

Altered Behavioral Responses Show GABA Sensitivity in Muscleblind-Like 2-Deficient Mice: Implications for CNS Symptoms in Myotonic Dystrophy

Abstract: We acknowledge support from NIH NINDS R01NS112291 (to GJB and ETW) and diversity supplement (KSE). This research was also in part supported by the Myotonic Dystrophy Foundation Pre-doctoral fellowship (KSE).

Cited by 3 publications

References 89 publications

Elucidating sleep disorders: a comprehensive bioinformatics analysis of functional gene sets and hub genes

Elucidating sleep disorders: a comprehensive bioinformatics analysis of functional gene sets and hub genes

Excessive rest time during active phase is reliably detected in a mouse model of myotonic dystrophy type 1 using home cage monitoring

Choroid plexus mis-splicing and altered cerebrospinal fluid composition in myotonic dystrophy type 1

Contact Info

Product

Resources

About