Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity


Huntington 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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Figure 1: Specific localization of huntingtin aggregates in HD-repeat mutant mouse brain.
Figure 2: Age-dependence of intranuclear and neuropil aggregates in HD-repeat mutant mice.
Figure 3: Huntingtin aggregates associated with N-terminal huntingtin fragments.
Figure 4: Comparison of huntingtin aggregates in R6/2 mice and HD-repeat mutant mice.
Figure 5: Effect of N-terminal huntingtin fragments on cultured striatal neurons.
Figure 6: Effect of N-terminal huntingtin fragments on synaptic vesicles and their glutamate uptake in vitro.


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We thank N. Ciliax for assistance in culturing striatal neurons; P. Thumfort for the GST–67Q DNA construct; C.A. Gutekunst and S. Hersch for antibody mHD549; and D. Danner for comments. This work was supported by grants from the NIH, Hereditary Disease Foundation, Huntington's Disease Society of America, and The Cunningham Trust (to P.F.S.).

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Correspondence to Xiao-Jiang Li.

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Li, H., Li, S., Johnston, H. et al. Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 25, 385–389 (2000).

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