Gigaxonin, mutated in Giant Axonal Neuropathy, interacts with TDP-43 and other RNA binding proteins

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Giant Axonal Neuropathy (GAN) is a neurodegenerative disorder stemming from mutations in the KLHL16 gene, which encodes gigaxonin.
• Gigaxonin deficiency impairs the turnover and transport of intermediate filament (IF) proteins, causing neuronal damage like axonal swelling and degeneration.
• The precise mechanisms underlying selective neuronal vulnerability in GAN remain unclear.

Purpose of the Study:

• To identify novel gigaxonin interactors relevant to GAN pathogenesis in neurons.
• To investigate the role of RNA-binding proteins (RBPs) in GAN-related neurodegeneration.

Main Methods:

• Unbiased proteomics was employed to identify proteins interacting with gigaxonin.
• Differential protein expression analysis was performed on induced pluripotent stem cell (iPSC)-derived neuron progenitors from a GAN patient.
• Immunofluorescence and co-localization studies were used to examine protein interactions in patient-derived iPSC-motor neurons.

Main Results:

• Proteomics analysis revealed a significant enrichment of RNA-binding proteins (RBPs) in the gigaxonin interactome and in GAN patient-derived neuron progenitors.
• TAR DNA-binding protein 43 (TDP-43) was identified as a gigaxonin interactor, binding to both the protein and its mRNA.
• TDP-43 was found to co-localize with neurofilament aggregates within swollen axons of iPSC-motor neurons from a GAN patient with an 'axonal CMT-plus' phenotype.

Conclusions:

• The findings suggest that RNA-binding protein dysfunction is a significant, potentially underappreciated, factor in GAN-related neurodegeneration.
• Interactions between gigaxonin and RBPs like TDP-43 may play a critical role in maintaining neuronal integrity and axonal transport.
• This research opens new avenues for understanding GAN pathophysiology and developing targeted therapeutic strategies.