Axonal Transport Defect in Gigaxonin Deficiency Rescued by Tubastatin A

Neurotherapeutics. 2023 Jul;20(4):1215-1228. doi: 10.1007/s13311-023-01393-1. Epub 2023 Jun 2.


Giant axonal neuropathy (GAN) is a disease caused by a deficiency of gigaxonin, a mediator of the degradation of intermediate filament (IF) proteins. A lack of gigaxonin alters the turnover of IF proteins, provoking accumulation and disorganization of neurofilaments (NFs) in neurons, a hallmark of the disease. However, the effects of IF disorganization on neuronal function remain unknown. Here, we report that cultured embryonic dorsal root ganglia (DRG) neurons derived from Gan-/- mice exhibit accumulations of IF proteins and defects in fast axonal transport of organelles. Kymographs generated by time-lapse microscopy revealed substantial reduction of anterograde movements of mitochondria and lysosomes in axons of Gan-/- DRG neurons. Treatment of Gan-/- DRG neurons with Tubastatin A (TubA) increased the levels of acetylated tubulin and it restored the normal axonal transport of these organelles. Furthermore, we tested the effects of TubA in a new mouse model of GAN consisting of Gan-/- mice with overexpression of peripherin (Prph) transgene. Treatment of 12-month-old Gan-/-;TgPer mice with TubA led to a slight amelioration of motor function, especially a significant improvement of gait performance as measured by footprint analyses. Moreover, TubA treatment reduced the abnormal accumulations of Prph and NF proteins in spinal neurons and it boosted the levels of Prph transported into peripheral nerve axons. These results suggest that drug inhibitors of histone deacetylase aiming to enhance axonal transport should be considered as a potential treatment for GAN disease.

Keywords: DRG Dorsal root ganglia; GAN Giant axonal neuropathy; Gan Gigaxonin; IF Intermediate filament; NF Neurofilament; Nefl Neurofilament light chain; Neuropathy; Prph Peripherin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axonal Transport
  • Axons / metabolism
  • Cytoskeletal Proteins* / metabolism
  • Ganglia, Spinal / metabolism
  • Giant Axonal Neuropathy* / metabolism
  • Giant Axonal Neuropathy* / therapy
  • Intermediate Filament Proteins / metabolism
  • Mice


  • Cytoskeletal Proteins
  • tubastatin A
  • Intermediate Filament Proteins