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

BMC Biol. 2020 Sep 16;18(1):127. doi: 10.1186/s12915-020-00845-w.


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: Endocytosis; Neurodegenerative disease; PLS3; SMA; SMN; hnRNP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / physiology
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Disease Models, Animal
  • Endocytosis / genetics
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Muscular Atrophy, Spinal / genetics*
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Survival of Motor Neuron 1 Protein / genetics*
  • Survival of Motor Neuron 1 Protein / metabolism


  • Caenorhabditis elegans Proteins
  • Membrane Glycoproteins
  • Microfilament Proteins
  • RNA-Binding Proteins
  • SMN1 protein, human
  • SYM-2 protein, C elegans
  • Survival of Motor Neuron 1 Protein
  • plastin