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Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport.

Abstract：

: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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Ding J,Allen E,Wang W,Valle A,Wu C,Nardine T,Cui B,Yi J,Taylor A,Jeon NL,Chu S,So Y,Vogel H,Tolwani R,Mobley W,Yang Y

doi

10.1093/hmg/ddl069

subject

Has Abstract

pub_date

2006-05-01 00:00:00

pages

1451-63

issue

9

eissn

0964-6906

issn

1460-2083

pii

ddl069

journal_volume

15

pub_type

杂志文章

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