Gigaxonin interacts with tubulin folding cofactor B and controls its degradation through the ubiquitin-proteasome pathway.
Gigaxonin is mutated in human giant axonal neuropathy (GAN), an autosomal recessive neurodegenerative disorder. The presence of generalized cytoskeletal abnormalities , including few microtubules and accumulated intermediate filaments (IFs), in GAN suggests an essential role of gigaxonin in cytoskeletal organization and dynamics. However, the molecular mechanisms underlying the cytoskeletal pathology remain to be elucidated. Over the years, the ubiquitin-proteasome system (UPS) of intracellular protein degradation has been implicated in the control of many fundamental cellular processes. Defects in this system seem to be directly linked to the development of human diseases, including cancers and neurodegenerative diseases . Here, we show that gigaxonin controls protein degradation of tubulin folding cofactor B (TBCB) , a function disrupted by GAN-associated mutations. The substantial TBCB protein accumulation caused by impaired UPS may be a causative factor of cytoskeletal pathology in GAN. Our study provides important insight into pathogenesis of neurodegenerative diseases associated with cytoskeletal abnormalities.
Wang
Wei
W
Department of Neurology and Neurological Sciences, Stanford University, 1201 Welch Road, MSLS P207, Stanford, California 94305, USA.
Ding
Jianqing
J
Allen
Elizabeth
E
Zhu
Ping
P
Zhang
Lan
L
Vogel
Hannes
H
Yang
Yanmin
Y
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D020798:Two-Hybrid System Techniques; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
D003598:Cytoskeletal Proteins; C416508:GAN protein, human; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; C501073:tubulin cofactor B, human; D043743:Ubiquitin-Protein Ligase Complexes