Degeneration of proprioceptive sensory nerve endings in mice harboring amyotrophic lateral sclerosis-causing mutations

J Comp Neurol. 2015 Dec 1;523(17):2477-94. doi: 10.1002/cne.23848. Epub 2015 Jul 21.


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much is known about the effects of ALS on motor neurons and glial cells, little is known about its effect on proprioceptive sensory neurons. This study examines proprioceptive sensory neurons in mice harboring mutations associated with ALS, in SOD1(G93A) and TDP43(A315T) transgenic mice. In both transgenic lines, we found fewer proprioceptive sensory neurons containing fluorescently tagged cholera toxin in their soma five days after injecting this retrograde tracer into the tibialis anterior muscle. We asked whether this is due to neuronal loss or selective degeneration of peripheral nerve endings. We found no difference in the total number and size of proprioceptive sensory neuron soma between symptomatic SOD1(G93A) and control mice. However, analysis of proprioceptive nerve endings in muscles revealed early and significant alterations at Ia/II proprioceptive nerve endings in muscle spindles before the symptomatic phase of the disease. Although these changes occur alongside those at α-motor axons in SOD1(G93A) mice, Ia/II sensory nerve endings degenerate in the absence of obvious alterations in α-motor axons in TDP43(A315T) transgenic mice. We next asked whether proprioceptive nerve endings are similarly affected in the spinal cord and found that nerve endings terminating on α-motor neurons are affected during the symptomatic phase and after peripheral nerve endings begin to degenerate. Overall, we show that Ia/II proprioceptive sensory neurons are affected by ALS-causing mutations, with pathological changes starting at their peripheral nerve endings.

Keywords: Amyotrophic Lateral Sclerosis (ALS); Motor neuron; Neuromuscular junction (NMJ); Proprioceptive sensory neuron; SOD1g93A; TDP43A315T; VAChT; VGLUT1.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Cholera Toxin / metabolism
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Mutation / genetics*
  • Nerve Degeneration* / genetics
  • Nerve Degeneration* / metabolism
  • Nerve Degeneration* / pathology
  • Nerve Tissue Proteins / metabolism
  • Parvalbumins / genetics
  • Parvalbumins / metabolism
  • Sensory Receptor Cells / metabolism*
  • Sensory Receptor Cells / pathology
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics*
  • Sympathetic Nervous System / metabolism
  • Sympathetic Nervous System / pathology
  • Synapses / metabolism
  • Synapses / pathology


  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Parvalbumins
  • TARDBP protein, human
  • Cholera Toxin
  • SOD1 G93A protein
  • Superoxide Dismutase