Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport.
Mutations in gigaxonin were identified in giant axonal neuropathy (GAN), an autosomal recessive disorder. To understand how disruption of gigaxonin's function leads to neurodegeneration, we ablated the gene expression in mice using traditional gene targeting approach. Progressive neurological phenotypes and pathological lesions that developed in the GAN null mice recapitulate characteristic human GAN features. The disruption of gigaxonin results in an impaired ubiquitin-proteasome system leading to a substantial accumulation of a novel microtubule-associated protein, MAP8, in the null mutants. Accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures and leads to neuronal death in cultured wild-type neurons, which replicates the process occurring in GAN null mutants. Defective axonal transport is evidenced by the in vitro assays and is supported by vesicular accumulation in the GAN null neurons. We propose that the axonal transport impairment may be a deleterious consequence of accumulated, toxic MAP8 protein.
Ding
Jianqing
J
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 1201 Welch Road, CA 94305-5489, USA.
Allen
Elizabeth
E
Wang
Wei
W
Valle
Angela
A
Wu
Chengbiao
C
Nardine
Timothy
T
Cui
Bianxiao
B
Yi
Jing
J
Taylor
Anne
A
Jeon
Noo Li
NL
Chu
Steven
S
So
Yuen
Y
Vogel
Hannes
H
Tolwani
Ravi
R
Mobley
William
W
Yang
Yanmin
Y
D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001923:Brain Chemistry / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004398:Dyneins / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D018390:Gene Targeting; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism* / Q000633:toxicity; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000737:chemistry / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure
D003598:Cytoskeletal Proteins; C501171:Gan protein, mouse; C512416:MAP8 protein, mouse; D008869:Microtubule-Associated Proteins; D004398:Dyneins