Early clinical and pre-clinical therapy development in Nemaline myopathy

Fisher, Gemma; Mackels, Laurane; Markati, Theodora; Sárközy, Anna; Ochala, Julien; Jungbluth, Heinz; Ramdas, Sithara; Servais, Laurent

doi:10.1080/14728222.2022.2157258

Cited by 6 publications

(5 citation statements)

References 135 publications

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“…Future studies should examine NM patient biopsy and electrophysiological results with more consideration for the specific gene mutated, which was not possible in previous decades. The DmCFL KD model should encourage further study into the role of the NMJ in NM disease progression and potential therapeutics (Fisher et al, 2022). There are reports from individual NM patients that use of acetylcholinesterase inhibitors can lead to clinical improvement (Natera-de Benito et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

Christophers,

Leahy,

Soffar

et al. 2023

Preprint

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Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shownDrosophilacofilin (DmCFL) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics byDmCFLknockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However,DmCFLknockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilin’s roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology.Summary statementCofilin regulates muscle postsynaptic actin organization, structural maintenance, glutamate receptor composition, and neuromuscular junction function in aDrosophilanemaline myopathy disease model.

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Section: Discussionmentioning

confidence: 99%

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

Christophers,

Leahy,

Soffar

et al. 2023

Preprint

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“…Additionally, as Shin et al showed that increased LAP1 levels correlated with milder phenotypes in emerin -null mice [ 38 ], LAP1 could reciprocally modulate other diseases phenotypes. Compensatory approaches that involve upregulating the expression of surrogate proteins to compensate for the absence of a specific protein have been proposed notably in Duchenne muscular dystrophy [ 95 ] and several congenital myopathy [ 96 ]. Exploring the potential of LAP1 overexpression to alleviate other disease phenotypes is a topic that warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

TOR1AIP1-Associated Nuclear Envelopathies

Mackels

Liu

Bonne

et al. 2023

IJMS

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Human TOR1AIP1 encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various biological processes and human diseases. The clinical spectrum of diseases related to mutations in TOR1AIP1 is broad, including muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease with or without progeroid features. Although rare, these recessively inherited disorders often lead to early death or considerable functional impairment. Developing a better understanding of the roles of LAP1 and mutant TOR1AIP1-associated phenotypes is paramount to allow therapeutic development. To facilitate further studies, this review provides an overview of the known interactions of LAP1 and summarizes the evidence for the function of this protein in human health. We then review the mutations in the TOR1AIP1 gene and the clinical and pathological characteristics of subjects with these mutations. Lastly, we discuss challenges to be addressed in the future.

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“…Muscle Contractile-Related ABPs in Myogenic Differentiation 3.8.1. α-Actinin α-Actinin, along with myosin IIs (NM IIs), nebulin, and tropomyosin, is a specific protein expressed in mature skeletal muscle tissue and is instrumental in muscle contraction when coupled with myosin motors [67][68][69][70]237]. These proteins, pivotal in the architecture and function of mature skeletal muscles, are also implicated in Nemaline myopathies (NM) and are under investigation for potential clinical therapies [237]. Their expression and function during myogenic differentiation emphasize their relevance as mature muscle genes.…”

Section: [F-actin]-monooxygenase Mical2mentioning

confidence: 99%

Role of Actin-Binding Proteins in Skeletal Myogenesis

Nguyen,

Dash,

Jeong

et al. 2023

Cells

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Maintenance of skeletal muscle quantity and quality is essential to ensure various vital functions of the body. Muscle homeostasis is regulated by multiple cytoskeletal proteins and myogenic transcriptional programs responding to endogenous and exogenous signals influencing cell structure and function. Since actin is an essential component in cytoskeleton dynamics, actin-binding proteins (ABPs) have been recognized as crucial players in skeletal muscle health and diseases. Hence, dysregulation of ABPs leads to muscle atrophy characterized by loss of mass, strength, quality, and capacity for regeneration. This comprehensive review summarizes the recent studies that have unveiled the role of ABPs in actin cytoskeletal dynamics, with a particular focus on skeletal myogenesis and diseases. This provides insight into the molecular mechanisms that regulate skeletal myogenesis via ABPs as well as research avenues to identify potential therapeutic targets. Moreover, this review explores the implications of non-coding RNAs (ncRNAs) targeting ABPs in skeletal myogenesis and disorders based on recent achievements in ncRNA research. The studies presented here will enhance our understanding of the functional significance of ABPs and mechanotransduction-derived myogenic regulatory mechanisms. Furthermore, revealing how ncRNAs regulate ABPs will allow diverse therapeutic approaches for skeletal muscle disorders to be developed.

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Early clinical and pre-clinical therapy development in Nemaline myopathy

Cited by 6 publications

References 135 publications

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

TOR1AIP1-Associated Nuclear Envelopathies

Role of Actin-Binding Proteins in Skeletal Myogenesis

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