Gigaxonin is required for intermediate filament transport

Area of Science:

• Cell Biology
• Neuroscience
• Biochemistry

Background:

• Gigaxonin is an adaptor protein crucial for ubiquitination and degradation of intermediate filament (IF) proteins.
• Mutations in the GAN gene, encoding gigaxonin, cause giant axonal neuropathy (GAN), characterized by IF accumulation.
• The precise mechanism driving IF aggregation in GAN remains unclear.

Purpose of the Study:

• To investigate the role of gigaxonin in the dynamics and transport of IFs.
• To elucidate the cause of IF aggregation in gigaxonin-deficient cells.

Main Methods:

• Utilized subunits of IFs tagged with the photoconvertible protein mEOS 3.2 to study IF dynamics.
• Assessed the impact of gigaxonin loss on the transport of IFs and other cargoes by the motor protein kinesin-1.
• Investigated rescue strategies for abnormal IF distribution.

Main Results:

• Gigaxonin deficiency significantly inhibited the transport of IFs along microtubules by kinesin-1.
• This transport inhibition was specific to IFs, while other kinesin-1 cargoes were unaffected.
• Direct binding of kinesin-1 to IFs rescued the abnormal IF distribution, confirming transport as the primary cause.
• Gigaxonin knockout cells showed a >20-fold increase in soluble vimentin oligomers.

Conclusions:

• Gigaxonin is essential for normal IF transport along microtubules via kinesin-1.
• Inhibition of IF transport, potentially due to increased soluble vimentin oligomers saturating an adapter protein, is the primary cause of IF aggregation in GAN.
• These findings provide a mechanistic link between gigaxonin function, IF transport, and the pathogenesis of giant axonal neuropathy.