Involvement of CRMP2 in Regulation of Mitochondrial Morphology and Motility in Huntington's Disease

Cells. 2021 Nov 15;10(11):3172. doi: 10.3390/cells10113172.


Mitochondrial morphology and motility (mitochondrial dynamics) play a major role in the proper functioning of distant synapses. In Huntington's disease (HD), mitochondria become fragmented and less motile, but the mechanisms leading to these changes are not clear. Here, we found that collapsin response mediator protein 2 (CRMP2) interacted with Drp1 and Miro 2, proteins involved in regulating mitochondrial dynamics. CRMP2 interaction with these proteins inversely correlated with CRMP2 phosphorylation. CRMP2 was hyperphosphorylated in postmortem brain tissues of HD patients, in human neurons derived from induced pluripotent stem cells from HD patients, and in cultured striatal neurons from HD mouse model YAC128. At the same time, CRMP2 interaction with Drp1 and Miro 2 was diminished in HD neurons. The CRMP2 hyperphosphorylation and dissociation from Drp1 and Miro 2 correlated with increased fission and suppressed motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Thr 509/514 and Ser 522 and rescued CRMP2's interaction with Drp1 and Miro 2. This was accompanied by reduced mitochondrial fission and enhanced mitochondrial motility. Additionally, (S)-LCM exerted a neuroprotective effect in YAC128 cultured neurons. Thus, our data suggest that CRMP2 may regulate mitochondrial dynamics in a phosphorylation-dependent manner and modulate neuronal survival in HD.

Keywords: CRMP2; Huntington’s disease; mitochondria; morphology; motility; neuron.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dynamins / metabolism
  • Female
  • Humans
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / pathology*
  • Mitochondrial Dynamics
  • Necrosis
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Phosphorylation
  • Postmortem Changes
  • Protein Binding


  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • collapsin response mediator protein-2
  • DNM1L protein, human
  • Dynamins