Impaired Local Translation of β-actin mRNA in Ighmbp2-Deficient Motoneurons: Implications for Spinal Muscular Atrophy with respiratory Distress (SMARD1)

Surrey, Verena; Zöller, Caren; Lork, Alicia Andrea; Moradi, Mehri; Balk, Stefanie; Dombert, Benjamin; Saal-Bauernschubert, Lena; Briese, Michael; Appenzeller, Silke; Fischer, Utz; Jablonka, Sibylle

doi:10.1016/j.neuroscience.2018.06.019

Cited by 11 publications

(17 citation statements)

References 62 publications

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“…Finally, Ighmbp2 deficiency in cultured nmd mouse primary motor neurons leads to a translational delay of β-actin mRNA and a selective reduction of protein levels in axonal growth cones. This is despite the fact that Ighmbp2 does not bind directly to β-actin mRNA and that no abnormalities were detected in the amount of the corresponding mRNA or the total protein level [41]. These findings reinforce the idea that IGHMBP2 is important for translation processes in the cell (Figure 2).…”

Section: Structure and Function Of Ighmbp2supporting

confidence: 60%

“…Importantly though, the functioning of ERI 6/7 as a IGHMBP2 homolog is in doubt. There is no evidence that IGHMBP2 also serves in RNAi processing and an Ighmbp2 deficiency only slightly alters the level of mRNAs and newly synthesized proteins in mouse primary cultured motor neurons [41]. This rather excludes IGHMBP2 from having a role in mRNA decay.…”

Section: Worm Caenorhabditis Elegansa Simple But Problematic Modelmentioning

confidence: 98%

“…Specific muscles are characterized by their different susceptibilities to denervation, with the muscles of the distal appendicular region exhibiting the highest degree of vulnerability [50]. In contrast to motor neurons derived from a mouse model of SMA, cultured embryonic nmd mutant motor neurons do not show any defects in terms of survival, axonal growth or growth cone size [37,41]. These findings suggest that the pathomechanism of SMARD1 is different from that of SMA [37,41].…”

Section: This Mouse Strain Possesses a Spontaneous Homozygous Mutation (A-g) In Intron 4 Of Thementioning

confidence: 99%

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Models for IGHMBP2-associated diseases: an overview and a roadmap for the future

Rzepnikowska

Kochański

2021

Neuromuscular Disorders

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Section: Structure and Function Of Ighmbp2supporting

confidence: 60%

Section: Worm Caenorhabditis Elegansa Simple But Problematic Modelmentioning

confidence: 98%

Section: This Mouse Strain Possesses a Spontaneous Homozygous Mutation (A-g) In Intron 4 Of Thementioning

confidence: 99%

See 1 more Smart Citation

Models for IGHMBP2-associated diseases: an overview and a roadmap for the future

Rzepnikowska

Kochański

2021

Neuromuscular Disorders

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“…Inefficient DNA repair machinery or more fragile translational machinery, possibly due to the extension of the axons and dendrites of MNs, are other intriguing explanations, but these explanations may be incorrect or describe just a part of other mechanisms. Consistent with this notion, Ighmbp2 deficiency in nmd motor neurons was recently correlated with alterations in protein biosynthesis, especially that of the β-actin protein [104]. β-actin is an abundant cytoskeletal protein, and aberrations in its regulation have been previously observed in Smn (survival motor neuron)-deficient motor neurons, suggesting that it plays a crucial role in cell development and differentiation [50,87].…”

Section: A Possible Role In Mrna Translationmentioning

confidence: 60%

“…β-actin is an abundant cytoskeletal protein, and aberrations in its regulation have been previously observed in Smn (survival motor neuron)-deficient motor neurons, suggesting that it plays a crucial role in cell development and differentiation [50,87]. Although Ighmbp2-deficient primary cultured motor neurons display a significant and selective reduction in β-actin protein levels in axonal growth cones, no abnormalities are detected in the amount of corresponding mRNA or total protein, indicating a translational delay [104]. These results may further indicate the involvement of IGHMBP2 in translation, although deeper studies are necessary to draw conclusions on its direct and indirect impacts.…”

Section: A Possible Role In Mrna Translationmentioning

confidence: 97%

Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Perego

Galli

Nizzardo

et al. 2020

Cell. Mol. Life Sci.

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Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.

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Novel biallelic nonsense mutation in IGHMBP2 gene linked to neuropathy (CMT2S): A comprehensive clinical, genetic and bioinformatic analysis of a Turkish patient with literature review

Yavas,

Dogan,

Ozgor

et al. 2025

Brain and Development

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Impaired Local Translation of β-actin mRNA in Ighmbp2-Deficient Motoneurons: Implications for Spinal Muscular Atrophy with respiratory Distress (SMARD1)

Cited by 11 publications

References 62 publications

Models for IGHMBP2-associated diseases: an overview and a roadmap for the future

Models for IGHMBP2-associated diseases: an overview and a roadmap for the future

Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Novel biallelic nonsense mutation in IGHMBP2 gene linked to neuropathy (CMT2S): A comprehensive clinical, genetic and bioinformatic analysis of a Turkish patient with literature review

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