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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Aggregation of N-terminal huntingtin is dependent on the length of its glutamine repeats
1Department of Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
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 various N-terminal fragments of mutant huntingtin can form aggregates and that aggregation is prompted by lengthening the glutamine repeat.
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