Axonal Transport Defect in Gigaxonin Deficiency Rescued by Tubastatin A

• DOI: 10.1007/s13311-023-01393-1
• Publication Date: 2023-06-02T18:02:10Z
• Authors: Banshi Nath; Daniel Phaneuf; Jean-Pierre Julien
• Keywords: Axoplasmic transport; Peripherin; HDAC6; Neurofilament; Organelle

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