Nature Genetics
25, 385 - 389 (2000)
doi:10.1038/78054
Amino-terminal fragments of mutant huntingtin show selective accumulation
in striatal neurons and synaptic toxicityHe Li1, 3, Shi-Hua Li1, Heather Johnston2, Peggy F. Shelbourne2
& Xiao-Jiang Li11
Department of Genetics, Emory University School of
Medicine, Atlanta, Georgia, USA. 2
Division of Molecular Genetics, Institute of Biomedical
and Life Sciences, University of Glasgow, Glasgow,
Scotland, UK. 3
Department of Histology and Embryology, Tongi Medical
University, Wuhan, P.R. China.
Correspondence should be addressed to Xiao-Jiang Li xiaoli@genetics.emory.eduHuntington disease (HD) is caused by expansion of a glutamine repeat in
the amino-terminal region of huntingtin. Despite its widespread expression,
mutant huntingtin induces selective neuronal loss in striatal neurons. Here
we report that, in mutant mice expressing HD repeats, the production and aggregation
of N-terminal huntingtin fragments preferentially occur in HD-affected neurons
and their processes and axonal terminals. N-terminal fragments of mutant huntingtin
form aggregates and induce neuritic degeneration in cultured striatal neurons.
N-terminal mutant huntingtin also binds to synaptic vesicles and inhibits
their glutamate uptake in vitro. The specific processing and accumulation
of toxic fragments of N-terminal huntingtin in HD-affected striatal neurons,
especially in their neuronal processes and axonal terminals, may contribute
to the selective neuropathology of HD.
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