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

Autor:	Maria Dimitriadi, Anne C. Hart, Melissa B. Walsh, Natalia Rodriguez Muela, Erika M. Norabuena, Seyyedmohsen Hosseinibarkooie, Eva Janzen, Brunhilde Wirth, Emily Wingrove, Lee L. Rubin, Lance S. Davidow
Rok vydání:	2020
Předmět:	Physiology Endocytic cycle Plant Science Neurodegenerative disease General Biochemistry Genetics and Molecular Biology Animals Genetically Modified Muscular Atrophy Spinal 03 medical and health sciences 0302 clinical medicine Structural Biology PLS3 medicine Animals SMA Caenorhabditis elegans Caenorhabditis elegans Proteins lcsh:QH301-705.5 Ecology Evolution Behavior and Systematics 030304 developmental biology 0303 health sciences Membrane Glycoproteins biology Microfilament Proteins RNA-Binding Proteins Survival of motor neuron Cell Biology Spinal muscular atrophy Motor neuron biology.organism_classification medicine.disease Survival of Motor Neuron 1 Protein Endocytosis Cell biology SMN Disease Models Animal medicine.anatomical_structure lcsh:Biology (General) General Agricultural and Biological Sciences 030217 neurology & neurosurgery Function (biology) Developmental Biology Biotechnology Research Article hnRNP
Zdroj:	BMC Biology BMC Biology, Vol 18, Iss 1, Pp 1-19 (2020)
ISSN:	1741-7007
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0ac0e4bf1b1a466bb2fdb09b325c77ba https://pubmed.ncbi.nlm.nih.gov/32938453 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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