Microtubule-associated protein 1B dysregulates microtubule dynamics and neuronal mitochondrial transport in spinal muscular atrophy

Hum Mol Genet. 2021 Feb 25;29(24):3935-3944. doi: 10.1093/hmg/ddaa275.

Abstract

Spinal muscular atrophy (SMA) is a devastating childhood disease primarily affecting lower motoneurons in the spinal cord. SMA is caused by the loss of functional survival of motoneuron (SMN) protein, leading to structural and functional alterations of the cytoskeleton in motoneurons and other cells. Loss of SMN results in impairments of microtubule architecture, but the underlying mechanisms are not completely understood. In this study, we mechanistically analyzed the effects of SMN deficiency on microtubules, demonstrating a reduced stability together with a reduction in alpha tubulin detyrosination. This was caused by increased levels of microtubule-associated protein 1B and tubulin tyrosine ligase, resulting in mitochondrial mislocalization in SMA. Our findings suggest that altered tubulin post-translational modifications and microtubule-associated proteins are involved in the pathomechanisms of SMA, such as an impaired axonal transport of mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axonal Transport
  • Biological Transport
  • Cells, Cultured
  • Humans
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / metabolism
  • Microtubules / pathology*
  • Mitochondria
  • Motor Neurons / metabolism
  • Motor Neurons / pathology*
  • Muscular Atrophy, Spinal / etiology
  • Muscular Atrophy, Spinal / metabolism
  • Muscular Atrophy, Spinal / pathology*
  • Mutation*
  • Peptide Synthases / genetics
  • Peptide Synthases / metabolism*
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 1 Protein / metabolism*
  • Tubulin / metabolism
  • Tyrosine / metabolism

Substances

  • Microtubule-Associated Proteins
  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein
  • Tubulin
  • microtubule-associated protein 1B
  • Tyrosine
  • Peptide Synthases
  • tyrosyltubulin ligase