Potential role of tubulin acetylation and microtubule-based protein trafficking in familial dysautonomia.
Familial dysautonomia (FD), a disease of the autonomic and sensory nervous systems, involves mutations in the protein IkappaB kinase complex-associated protein, which is a component of the human Elongator acetylase complex. We suggest a hypothesis in which defects in tubulin acetylation and impairment of microtubule-based protein trafficking may be an underlying cause of FD. In addition, an Arabidopsis homolog of the Elongator subunit ELP3 has been found to bind to the alphabeta-tubulin heterodimer, suggesting that alpha-tubulin may be a cytoplasmic target of Elongator acetylase activity. Studies of synergistic double mutants in yeast indicate a novel role for Elongator in cytoskeletal dynamics, although this is probably because of an effect on actin rather than microtubules. Finally, we suggest that tubulin deacetylase inhibitors may prove useful in the treatment of FD.
Gardiner
John
J
School of Biological Sciences, Macleay Building (A12), Science Road, The University of Sydney, Camperdown 2006, Australia. jgardiner@usyd.edu.au
Barton
Deborah
D
Marc
Jan
J
Overall
Robyn
R
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004402:Dysautonomia, Familial / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D051548:Histone Acetyltransferases / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D035602:Transcriptional Elongation Factors; D014404:Tubulin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C114720:Elp1 protein, human; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D035602:Transcriptional Elongation Factors; D014404:Tubulin; D051548:Histone Acetyltransferases; D048670:MAP Kinase Kinase 4; D006655:Histone Deacetylases