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Cited by 22Neurogenetic and Muscular Disorders ResearchAmyotrophic Lateral Sclerosis ResearchHereditary Neurological Disorders

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Genetic modifiers ameliorate endocytic and neuromuscular defects in a model of spinal muscular atrophy

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Walsh, Melissa B., Janzen, Eva, Wingrove, Emily, Hosseinibarkooie, Seyyedmohsen, Muela, Natalia Rodriguez, Davidow, Lance, Dimitriadi, Maria, Norabuena, Erika M., Rubin, Lee L., Wirth, Brunhilde, Hart, Anne C.·2020·BMC Biology
DOI 10.1186/s12915-020-00845-wPMC PMC7495824
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Abstract

Background: Understanding the genetic modifiers of neurodegenerative diseases can provide insight into the mechanisms underlying these disorders. Here, we examine the relationship between the motor neuron disease spinal muscular atrophy (SMA), which is caused by reduced levels of the survival of motor neuron (SMN) protein, and the actin-bundling protein Plastin 3 (PLS3). Increased PLS3 levels suppress symptoms in a subset of SMA patients and ameliorate defects in SMA disease models, but the functional connection between PLS3 and SMN is poorly understood. Results: We provide immunohistochemical and biochemical evidence for large protein complexes localized in vertebrate motor neuron processes that contain PLS3, SMN, and members of the hnRNP F/H family of proteins. Using a Caenorhabditis elegans ( C. elegans ) SMA model, we determine that overexpression of PLS3 or loss of the C. elegans hnRNP F/H ortholog SYM-2 enhances endocytic function and ameliorates neuromuscular defects caused by decreased SMN-1 levels. Furthermore, either increasing PLS3 or decreasing SYM-2 levels suppresses defects in a C. elegans ALS model. Conclusions: We propose that hnRNP F/H act in the same protein complex as PLS3 and SMN and that the function of this complex is critical for endocytic pathways, suggesting that hnRNP F/H proteins could be potential targets for therapy development.

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  • Previous studies have shown that modifier genes, such as nuclear hormone receptors, have the potential to reset various networks related to retinal disease phenotypes, such as photoreceptor development, phototransduction, metabolism, cone cell development, inflammation, and cell survival, thus restoring homeostasis in the retina to a healthy state.

    “Previous studies have shown that modifier genes, such as nuclear hormone receptors, have the potential to “reset” various networks related to retinal disease phenotypes, such as photoreceptor development, phototransduction, metabolism, cone cell development, inflammation, and cell survival, thus restoring the homeostasis in the retina to a healthy state.47,50–53”

    From Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions (2023) · cites this paper as [50]

  • Modifier gene therapy has the potential to alter the retinal disease state even in the absence of a genetic diagnosis or in the absence of a gene therapy specific to the mutated gene.

    “Modifier gene therapy has the potential to alter the retinal disease state even in the absence of a genetic diagnosis or in the absence of a gene therapy specific to the mutated gene in one of these patients.47,50–53”

    From Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions (2023) · cites this paper as [50]

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Authors
Walsh, M. B., Janzen, E., Wingrove, E., Hosseinibarkooie, S., Muela, N. R., Davidow, L., Dimitriadi, M., Norabuena, E. M., Rubin, L. L., Wirth, B., & Hart, A. C.
Affiliations
  • Brown University (US)
  • University of Cologne (DE)
  • Harvard University (US)
  • University of Hertfordshire (GB)
Corresponding author
Hart, Anne C.
ORCID
Venue
BMC Biology
Publisher
Springer Science and Business Media LLC
Published
2020-09-16
Volume
18
Issue
1
Pages
127-127
ISSN
1741-7007 (ISSN-L)
DOI
10.1186/s12915-020-00845-w
PMC
PMC7495824
OpenAlex
W3087321818
Cited by
22
References
2
Citations by year
2026: 3 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 1 · 2021: 5
FWCI
1.55
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • University of Hertfordshire Research Archive (University of Hertfordshire) (acceptedVersion)
  • University of Hertfordshire Research Archive (University of Hertfordshire) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Hertfordshire Research Archive (University of Hertfordshire) (submittedVersion, cc-by)
Funders
  • NIH Office of the Director (P40 OD010440)
  • National Institute of Neurological Disorders and Stroke (P01 N5066888)
  • Deutsche Forschungsgemeinschaft (Wi-945/16-1, Wi 945/17-1, Wi-945/18-1 and RTG 1960)
  • Center for Molecular Medicine Cologne (C16)
Topics
  • Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
spinal muscular atrophy, survival motor neuron protein, PLS3, genetic modifiers, endocytosis, motor neuron disease, amyotrophic lateral sclerosis, Caenorhabditis elegans model, protein complexes, actin bundling
MeSH terms
Animals, Disease Models, Animal, Endocytosis, Membrane Glycoproteins, Microfilament Proteins, Muscular Atrophy, Spinal, RNA-Binding Proteins, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Animals, Genetically Modified, Survival of Motor Neuron 1 Protein

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