Genetic modifiers ameliorate endocytic and neuromuscular defects in a model of spinal muscular atrophy
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RESEARCH ARTICLE
Open Access
Genetic modifiers ameliorate endocytic and neuromuscular defects in a model of spinal muscular atrophy Melissa B. Walsh1, Eva Janzen2, Emily Wingrove1, Seyyedmohsen Hosseinibarkooie2, Natalia Rodriguez Muela3, Lance Davidow3, Maria Dimitriadi4, Erika M. Norabuena3, Lee L. Rubin3, Brunhilde Wirth2 and Anne C. Hart1*
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. Keywords: PLS3, hnRNP, Neurodegenerative disease, SMN, SMA, Endocytosis
Background Neurodegenerative diseases are widespread and usually incurable. The identity of disease-causing genes is frequently known, but the mechanisms and pathways underlying disease onset, progression, and pathology remain elusive. The motor neuron disease spinal muscular atrophy (SMA) is caused by reduced levels of the survival of motor neuron (SMN) protein. * Correspondence: [email protected] 1 Department of Neuroscience, Brown University, 185 Meeting Street, Mailbox GL-N, Providence, RI 02912, USA Full list of author information is available at the end of the article
Decreased SMN in SMA patients impacts the function of alpha motor neurons, resulting in their dysfunction, degeneration, and consequent muscular atrophy. SMN is required for the biogenesis of small nuclear ribonucleoproteins (snRNPs), which are critical for pre-mRNA splicing [1–3]. SMN is also found in stress granules and other RNP granules in neuronal processes [4–7], and other studies have identified roles for SMN in microRNA biogenesis and endocytic pathways [8–11]. Determining which of these various granules and RNP-related pathways are most pertinent to SMA pathogenesis is critical. To dissect this,
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