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Alteration of actin cytoskeletal organisation in fetal akinesia deformation sequence.

ABSTRACT: Fetal akinesia deformation sequence (FADS) represents the severest form of congenital myasthenic syndrome (CMS), a diverse group of inherited disorders characterised by impaired neuromuscular transmission. Most CMS originate from defects in the muscle nicotinic acetylcholine receptor, but the underlying molecular pathogenesis is only poorly understood. Here we show that RNAi-mediated silencing of FADS-related proteins rapsyn and NUP88 in foetal fibroblasts alters organisation of the actin cytoskeleton. We show that fibroblasts from two independent FADS individuals have enhanced and shorter actin stress fibre bundles, alongside with an increased number and size of focal adhesions, with an otherwise normal overall connectivity and integrity of the actin-myosin cytoskeleton network. By proximity ligation assays and bimolecular fluorescence complementation, we show that rapsyn and NUP88 localise nearby adhesion plaques and that they interact with the focal adhesion protein paxillin. Based on these findings we propose that a respective deficiency in rapsyn and NUP88 in FADS alters the regulation of actin dynamics at focal adhesions, and thereby may also plausibly dictate myofibril contraction in skeletal muscle of FADS individuals.

SUBMITTER: Juhlen R

PROVIDER: S-EPMC10799014 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Alteration of actin cytoskeletal organisation in fetal akinesia deformation sequence.

Jühlen Ramona R Grauer Lukas L Martinelli Valérie V Rencurel Chantal C Fahrenkrog Birthe B

Scientific reports 20240119 1

Fetal akinesia deformation sequence (FADS) represents the severest form of congenital myasthenic syndrome (CMS), a diverse group of inherited disorders characterised by impaired neuromuscular transmission. Most CMS originate from defects in the muscle nicotinic acetylcholine receptor, but the underlying molecular pathogenesis is only poorly understood. Here we show that RNAi-mediated silencing of FADS-related proteins rapsyn and NUP88 in foetal fibroblasts alters organisation of the actin cytosk ...[more]

PMID: 38242956

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Project description:The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members synthesize the electron carrier nicotinamide adenine dinucleotide (NAD+) and are essential for cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also function as a chaperone to aid in the refolding of misfolded proteins. Nmnat2 deficiency in mice, or in its ortholog dNmnat in Drosophila, results in axon outgrowth and survival defects. Peripheral nerve axons in NMNAT2-deficient mice fail to extend and innervate targets, and skeletal muscle is severely underdeveloped. In addition, removing NMNAT2 from established axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings with fetal akinesia deformation sequence (FADS), severely reduced skeletal muscle mass and hydrops fetalis. Clinical exome sequencing identified compound heterozygous NMNAT2 variant alleles in both cases. Both protein variants are incapable of supporting axon survival in mouse primary neuron cultures when overexpressed. In vitro assays demonstrate altered protein stability and/or defects in NAD+ synthesis and chaperone functions. Thus, both patient NMNAT2 alleles are null or severely hypo-morphic. These data indicate a previously unknown role for NMNAT2 in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder. SIGNIFICANCE: Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) both synthesizes the electron carrier Nicotinamide Adenine Dinucleotide (NAD+) and acts a protein chaperone. NMNAT2 has emerged as a major neuron survival factor. Overexpression of NMNAT2 protects neurons from Wallerian degeneration after injury and declining levels of NMNAT2 have been implicated in neurodegeneration. While the role of NMNAT2 in neurodegeneration has been extensively studied, the role of NMNAT2 in human development remains unclear. In this work, we present the first human variants in NMNAT2 identified in two fetuses with severe skeletal muscle hypoplasia and fetal akinesia. Functional studies in vitro showed that the mutations impair both NMNAT2 NAD+ synthase and chaperone functions. This work identifies the critical role of NMNAT2 in human development.

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Alteration of actin cytoskeletal organisation in fetal akinesia deformation sequence.

Publications

Alteration of actin cytoskeletal organisation in fetal akinesia deformation sequence.

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