Duchenne muscular dystrophy: recent insights in brain related comorbidities

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 3, 2025

Duchenne muscular dystrophy (DMD), the most common childhood dystrophy, arises from DMD gene mutations, affecting production of muscle dystrophin protein. Brain dystrophin-gene products are also transcribed via internal promoters. Their deficiency contributes to comorbidities, including intellectual disability ( ~ 22% patients), autism 6%) and attention deficit disorders 18%), representing a major unmet need for patients families. Thus, improvement their diagnosis treatment is needed. Dystrophic mouse models exhibit similar phenotypes, where genetic therapies restoring brain dystrophins improve behaviour. This suggests that future could address both dysfunction in patients.

Language: Английский

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Stress exposure in the mdx mouse model of Duchenne muscular dystrophy provokes a widespread metabolic response

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Duchenne muscular dystrophy is a severe neuromuscular wasting disease that caused by primary defect in dystrophin protein and involves organism‐wide comorbidities such as cardiomyopathy, metabolic mitochondrial dysfunction, nonprogressive cognitive impairments. Physiological stress exposure the mdx mouse model of results phenotypic abnormalities include locomotor inactivity, hypotension, increased morbidity. Severe lethal susceptibility mice corresponds to dysfunction several coordinated pathways within dystrophin‐deficient skeletal muscle, well prolonged elevation plasma corticosterone levels extends beyond wild‐type (WT) response. Here, we performed targeted mass spectrometry‐based metabolomics screen focused on biological healthy exposed mild scruff stress. One‐third stress‐relevant metabolites interrogated displayed significant or depletion after were restored WT muscle‐specific expression. The altered are associated with regulation hypothalamic–pituitary–adrenal axis, tone, neurocognitive function, redox metabolism, cellular bioenergetics, catabolism. Our data suggest triggers an exaggerated, multi‐system response mice.

Language: Английский

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Spatiotemporal diversity in molecular and functional abnormalities in the mdx dystrophic brain

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: March 20, 2025

Abstract Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration and neuropsychiatric abnormalities. Loss of full-length dystrophins both necessary sufficient to initiate DMD. These isoforms are expressed in the hippocampus, cerebral cortex (Dp427c), cerebellar Purkinje cells (Dp427p). However, our understanding consequences their absence, which crucial for developing targeted interventions, remains inadequate. We combined RNA sequencing with genome-scale metabolic modelling (GSMM), immunodetection, mitochondrial assays investigate dystrophic alterations brains mdx mouse model The cerebra cerebella were analysed separately discern roles Dp427c Dp427p, respectively. Investigating these regions at 10 days (10d) weeks (10w) followed evolution abnormalities from development early adulthood. time points also encompass periods before onset during inflammation, enabling assessment potential damage caused inflammatory mediators crossing blood–brain barrier. For first time, we demonstrated that transcriptomic functional unique vary substantially between 10d 10w. common anomalies involved altered numbers retained introns spliced exons across transcripts, corresponding mRNA processing pathways. Abnormalities significantly more pronounced younger mice. top enriched pathways included those related metabolism, processing, neuronal development. GSMM indicated dysregulation glucose corresponded GLUT1 protein downregulation. transcriptome, while altered, showed an opposite trajectory cerebra, few changes identified days. late defects specific indicate impact on maturation occurs postnatally. Although no classical neuroinflammation markers or microglial activation detected weeks, differences inflammation impacts DMD brains. Importantly, some occur may therefore be amenable therapeutic intervention, offering avenues mitigating DMD-related defects.

Language: Английский

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The unconditioned fear response in vertebrates deficient in dystrophin

Progress in Neurobiology, Journal Year: 2024, Volume and Issue: 235, P. 102590 - 102590

Published: March 12, 2024

Dystrophin loss due to mutations in the Duchenne muscular dystrophy (DMD) gene is associated with a wide spectrum of neurocognitive comorbidities, including an aberrant unconditioned fear response stressful/threat stimuli. Dystrophin-deficient animal models DMD demonstrate enhanced stress reactivity that manifests as sustained periods immobility. When threat repetitive or severe nature, dystrophinopathy phenotypes can be exacerbated and even cause sudden death. Thus, it apparent sensitivity stimuli dystrophin-deficient vertebrates legitimate concern for patients could impact neurocognition pathophysiology. This review discusses our current understanding mechanisms consequences hypersensitive preclinical potential challenges facing clinical translatability.

Language: Английский

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Retention of stress susceptibility in the mdx mouse model of Duchenne muscular dystrophy after PGC-1α overexpression or ablation of IDO1 or CD38

Human Molecular Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 5, 2024

Abstract Duchenne muscular dystrophy (DMD) is a lethal degenerative muscle wasting disease caused by the loss of structural protein dystrophin with secondary pathological manifestations including metabolic dysfunction, mood and behavioral disorders. In mildly affected mdx mouse model DMD, brief scruff stress causes inactivity, while more severe subordination results in lethality. Here, we investigated kynurenine pathway tryptophan degradation nicotinamide adenine dinucleotide (NAD+) mice their involvement as possible mediators stress-related pathology. We identified downregulation kynurenic acid shunt, neuroprotective branch pathway, skeletal associated attenuated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) transcriptional regulatory activity. Restoring shunt muscle-specific PGC-1α overexpression did not prevent -induced nor abrogating extrahepatic activity genetic deletion rate-limiting enzyme, indoleamine oxygenase 1. further show that reduced NAD+ production after exposure corresponded elevated levels catabolites produced ectoenzyme cluster differentiation 38 (CD38) have been implicated response to pharmacological β-adrenergic receptor agonism. However, CD38 ablation scruff-induced inactivity. Our data do support direct contribution or dysfunction exaggerated mice.

Language: Английский

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The bench to bedside journey of tricyclo-DNA antisense oligonucleotides for the treatment of Duchenne muscular dystrophy

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(9), P. 3017 - 3025

Published: Jan. 1, 2024

The development of antisense oligonucleotide (ASO)-based therapeutics has made tremendous progress over the past few years, in particular for treatment neuromuscular disorders such as Duchenne muscular dystrophy and spinal atrophy. Several ASO drugs have now reached market approval these diseases many more are currently under clinical evaluation. Among them, ASOs tricyclo-DNA originally developed by Christian Leumann shown particularly interesting properties demonstrated promise dystrophy. In this review, we examine bench to bedside journey tricyclo-DNA-ASOs from their early preclinical evaluation fully phosphorotiated-ASOs latest generation lipid-conjugated-ASOs. Finally discuss remaining challenges ASO-mediated exon-skipping therapy DMD future perspectives promising chemistry ASOs.

Language: Английский

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Networking to Optimize Dmd exon 53 Skipping in the Brain of mdx52 Mouse Model

Biomedicines, Journal Year: 2023, Volume and Issue: 11(12), P. 3243 - 3243

Published: Dec. 7, 2023

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that disrupt open reading frame and thus prevent production of functional dystrophin proteins. Recent advances treatment, notably exon skipping AAV therapy, have achieved some success aimed at alleviating symptoms related to progressive muscle damage. However, they do not address brain comorbidities associated with DMD, which remains a critical aspect disease. The mdx52 mouse model recapitulates one most frequent genetic pathogenic variants involvement DMD. Deletion 52 impedes expression two dystrophins, Dp427 Dp140, expressed from distinct promoters. Interestingly, this mutation eligible for strategies excluding 51 or 53 mRNA. We previously showed can restore partial internally deleted yet following intracerebroventricular (ICV) injection antisense oligonucleotides (ASO). This was improvement anxiety traits, unconditioned fear response, Pavlovian learning memory model. In present study, we investigated same order both Dp140. contrast 51, found particularly difficult mice combination multiple ASOs had be used simultaneously reach substantial levels skipping, regardless their chemistry (tcDNA, PMO, 2'MOE). Following ICV ASO sequences, measured up 25% hippocampus treated mice, but did elicit significant protein restoration. These findings indicate challenging. As such, it has been possible answer pertinent question whether rescuing Dp140 imperative more optimal treatment neurological aspects dystrophinopathy.

Language: Английский

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Levels of Exon-Skipping Are Not Artificially Overestimated Because of the Increased Affinity of Tricyclo-DNA-Modified Antisense Oligonucleotides to the Target DMD Exon

Nucleic Acid Therapeutics, Journal Year: 2024, Volume and Issue: 34(5), P. 214 - 220

Published: July 24, 2024

Antisense oligonucleotides (ASO) are very promising drugs for numerous diseases including neuromuscular disorders such as Duchenne muscular dystrophy (DMD). Several ASO have already been approved by the US Food and Drug Administration DMD global efforts still ongoing to improve further their potency, notably developing new delivery systems or alternative chemistries. In this context, a recent study investigated potential of different chemically modified induce exon-skipping in mouse models DMD. Importantly, authors reported strong discrepancy between protein restoration levels, which was mainly owing high affinity locked nucleic acid (LNA) modifications target RNA, thereby interfering with amplification unskipped product resulting artificial overamplification exon-skipped product. These findings urged us verify whether similar phenomenon could occur tricyclo-DNA (tcDNA)-ASO that also display high-affinity properties RNA. We thus ran series control experiments demonstrate here levels not overestimated an interference tcDNA-ASO contrast what observed LNA-containing ASO.

Language: Английский

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The role of dystrophin isoforms and interactors in the brain

Brain, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 28, 2024

Abstract Dystrophin is a protein crucial for maintaining the structural integrity of skeletal muscle. So far, attention was focused on role dystrophin in muscle view devastating progression weakness and early death that characterises Duchenne muscular dystrophy. However, last few years, shorter isoforms, including development adult expression-specific mechanisms, has been greater focus. Within cerebral landscape, various cell types, such as glia, oligodendrocytes, Purkinje cells, cerebellar granule vascular-associated cells express spectrum Dp427, Dp140, Dp71, Dp40. The interaction these isoforms with multitude proteins, suggests their involvement neurotransmission, influencing several circuit functions. This review presents intricate interactions among diverse complexes across different types brain regions, associated clinical complications. We focus studies investigating past 30 at biochemical level. In essence, brain's landscape thrilling exploration diversity, challenging preconceptions opening new avenues understanding central nervous system physiology. It also holds potential therapeutic implications neurological complications which deficiency involved. By revealing molecular complexities related to dystrophin, this paves way future investigations interventions aspect

Language: Английский

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Impact of distinct dystrophin gene mutations on behavioral phenotypes of Duchenne muscular dystrophy

Disease Models & Mechanisms, Journal Year: 2024, Volume and Issue: 17(12)

Published: Dec. 1, 2024

ABSTRACT The severity of brain comorbidities in Duchenne muscular dystrophy (DMD) depends on the mutation position within DMD gene and differential loss distinct dystrophin isoforms (i.e. Dp427, Dp140, Dp71). Comparative studies mouse models with different profiles may help to understand this genotype−phenotype relationship. aim study was (1) compare phenotypes due Dp427 mdx5cv mice those mdx52 mice, which concomitantly lack Dp140; (2) evaluate replicability separate laboratories. We show that displayed impaired fear conditioning robust anxiety-related responses, higher mice. Depression-related presented variably these were difficult replicate between Recognition memory unaltered or minimally affected at variance cognitive deficits described original Dp427-deficient mdx mouse, suggesting a difference related its genetic background. Our results confirm Dp140 increase emotional disturbances, provide insights limits reproducibility behavioral models.

Language: Английский

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