Aggregation of N-terminal huntingtin is dependent on the length of its glutamine repeats

Author： Li S-H.   Li X-J.  

Publisher： Oxford University Press

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.7, Iss.5, 1998-05, pp. : 777-782

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Abstract

Huntington's disease (HD) is caused by expansion of a glutamine repeat in huntingtin. Mutant huntingtin contains 36–55 repeats in adult HD patients and >60 repeats in juvenile HD patients. An N-terminal fragment of mutant huntingtin forms aggregates in neuronal nuclei in the brains of transgenic mice and HD patients. Aggregation of expanded polyglutamine is thought to be a common pathological mechanism in HD and other glutamine repeat diseases. It is not clear how the length of the repeats is correlated with formation of protein aggregates. By expressing a series of huntingtin constructs encoding various glutamine repeats (23–150 units) in cultured cells we observed N-terminal fragments of huntingtin (amino acids 1–67 and 1–212), but not full-length huntingtins, with glutamine repeats ≥66 units formed protein aggregates. Huntingtin aggregation was not induced when the repeat was ≤49 units and was markedly promoted by very long repeats ≥120 units. This study suggests that variousN-terminal fragments of mutant huntingtin can form aggregates and that aggregation is prompted by lengthening the glutamine repeat.

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