Duchenne muscular dystrophy: recent insights in brain related comorbidities

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 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.

Язык: Английский

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The many roles of dystroglycan in nervous system development and function

Developmental Dynamics, Год журнала: 2022, Номер 252(1), С. 61 - 80

Опубликована: Июнь 30, 2022

The glycoprotein dystroglycan was first identified in muscle, where it functions as part of the dystrophin complex to connect extracellular matrix actin cytoskeleton. Mutations genes involved glycosylation cause a form congenital muscular dystrophy termed dystroglycanopathy. In addition its well-defined role regulating muscle integrity, is essential for proper central and peripheral nervous system development. Patients with dystroglycanopathy can present wide range neurological perturbations, but unraveling Dag1 has proven be challenge. Over past two decades, animal models have been an invaluable resource that allowed researchers elucidate dystroglycan's many roles neural circuit this review, we summarize pathways known interacting proteins, discuss how regulates neuronal migration, axon guidance, synapse formation, non-neuronal cells.

Язык: Английский

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Dystrophin Short Product, Dp71, Interacts with AQP4 and Kir4.1 Channels in the Mouse Cerebellar Glial Cells in Contrast to Dp427 at Inhibitory Postsynapses in the Purkinje Neurons

Molecular Neurobiology, Год журнала: 2023, Номер 60(7), С. 3664 - 3677

Опубликована: Март 15, 2023

Язык: Английский

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Conditional Dystrophin ablation causes profound effects on muscle development, neurobehavior, and extracellular matrix pathways

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Abstract Duchenne muscular dystrophy (DMD) patients suffer from skeletal and cardiopulmonary weakness, interestingly up to one third are diagnosed on the autism spectrum. Dystrophin is an essential protein for regulating transmission of intracellular force extracellular matrix within muscle, but also plays key roles in neurobehavior cognitive function. The mouse dystrophin gene (also abbreviated Dmd ) X-linked has several isoforms with tissue-specific expression, including large Dp427m muscle transcript found heart Dp427c that encodes brain-specific cerebellar protein. Understanding functional requirements pathways affected by loss will impact replacement therapy exon-skipping correction strategies. We generated conditional knockout mice targeting exon 52 ( flox52 locus. constitutive inducible myofiber mKO) evaluate function isoform. Constitutive embryonic deletion exclusively myofibers resulted a severe myopathy, dystrophic histopathology, deficits compared mdx mouse. Transcriptomic analysis mKO revealed dysregulation cytokine signaling pathways. Separately, we Purkinje neuron :Pcp2 KO) displayed neurobehavioral social approach, memory, spatial navigation working memory. These studies reveal requirement expression both brain normal physiological Significance Statement caused lack muscle. (Dp427m) isoform expressed skeletal, cardiac, smooth its remain unknown. characterized mKO). genetic ablation histopathologies similar mouse, while postnatal milder pathologies. Ablating using Pcp2/L7 -Cre driver sociobehavioral defects. showed reduction Our study reveals role identifies modulation dystrophin-replacement therapies.

Язык: Английский

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Distinct functional domains of Dystroglycan regulate inhibitory synapse formation and maintenance in cerebellar Purkinje cells

Communications Biology, Год журнала: 2025, Номер 8(1)

Опубликована: Июнь 5, 2025

Dystroglycan is a cell adhesion molecule that localizes to synapses throughout the nervous system. While required maintain inhibitory from cerebellar molecular layer interneurons (MLIs) onto Purkinje cells (PCs) whether initial synaptogenesis during development dependent on has not been examined. We show mice with conditional deletion of prior results in impaired MLI:PC synapse formation and function due reduced presynaptic inputs abnormal postsynaptic GABAA receptor clustering. Using genetic manipulations disrupt glycosylation or truncate its cytoplasmic domain, we Dystroglycan's role requires both extracellular intracellular interactions, whereas only interactions. Together, these findings provide insight into mechanism maintenance cortex.

Язык: Английский

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Kit Ligand and Kit receptor tyrosine kinase sustain synaptic inhibition of Purkinje cells

eLife, Год журнала: 2024, Номер 12

Опубликована: Март 27, 2024

The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine functional relevance the long-established mutually exclusive receptor tyrosine kinase Kit trans-membrane protein Ligand by discrete populations in mammalian brain. enriched molecular layer interneurons (MLIs) cerebellar cortex (i.e., stellate basket cells), while selectively expressed target their inhibition, Purkinje cells (PCs). By vivo genetic manipulation spanning embryonic development adulthood, demonstrate that PC MLI are required for, capable driving changes in, inhibition PCs. Collectively, these works mice Ligand/Kit dyad sustains central synapse function suggest rationale for affiliation mutation with neurodevelopmental disorders.

Язык: Английский

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Altered Synaptic Transmission and Excitability of Cerebellar Nuclear Neurons in a Mouse Model of Duchenne Muscular Dystrophy

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Июль 5, 2022

Duchenne muscular dystrophy (DMD) is generally regarded as a muscle-wasting disease. However, human patients and animal models of DMD also frequently display non-progressive cognitive deficits high comorbidity with neurodevelopmental disorders, suggesting impaired central processing. Previous studies have identified the cerebellar circuit, aberrant inhibitory transmission in Purkinje cells, particular, potential site dysfunction nervous system (CNS). In this work, we investigate output cerebellum, downstream cell (PC) activity. We examined synaptic firing behavior excitatory projection neurons nuclei, primary juvenile wild-type mdx mice, common mouse model DMD. Using immunolabeling electrophysiology, found reduced number PC contacts, but no change postsynaptic GABA A receptor expression or clustering these cells. Furthermore, that replenishment rate vesicles terminals neurons, at synapses may be primarily presynaptic. changes excitability nuclear neurons. Specifically, greater spontaneous evoked from hyperpolarized baseline Analysis action waveforms revealed faster repolarization after-hyperpolarization potentials an increased voltage- calcium- gated potassium current. did not find evidence dystrophin protein messenger RNA (mRNA) observed cells are likely due to loss presynaptic PCs. Together, data suggest reduces dynamic range potentially disrupting circuit other brain regions contributing associated

Язык: Английский

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Abnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(20), С. 12617 - 12617

Опубликована: Окт. 20, 2022

Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of full-length Dp427 dystrophin in both muscle and brain. The basis central comorbidities DMD unclear. Brain plays role clustering gamma-aminobutyric acid A receptors (GABAARs), its mdx mouse alters some synaptic subunits inhibitory synapses. However, diversity GABAergic alterations this model still fragmentary. In study, analysis vivo PET imaging benzodiazepine-binding site radioligand revealed that global density GABAARs unaffected compared with WT mice. contrast, semi-quantitative immunoblots immunofluorescence confocal tissue sections complex differential patterns expression levels and/or clustered distribution variety extrasynaptic GABAAR hippocampus, cerebellum, cortex, spinal cord. Hence, not only affects stabilization but also influences subunit composition subtypes at sites. This study provides new molecular outcome measures routes to evaluate impact treatments aimed compensating nervous system DMD.

Язык: Английский

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Cerebellar dysfunction in the mdx mouse model of Duchenne muscular dystrophy: An electrophysiological and behavioural study

European Journal of Neuroscience, Год журнала: 2024, Номер 60(10), С. 6470 - 6489

Опубликована: Окт. 16, 2024

Patients with Duchenne muscular dystrophy (DMD) commonly show specific cognitive deficits in addition to a severe muscle impairment caused by the absence of dystrophin expression skeletal muscle. These have been related regions central nervous system, notably cerebellar Purkinje cells (PCs). Dystrophin has recently involved GABA

Язык: Английский

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The role of dystrophin isoforms and interactors in the brain

Brain, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 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

Язык: Английский

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