Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Huntington's disease (HD) is an inherited, neurodegenerative disordercaused by the expansion of a glutamine repeat in the N-terminus of thehuntingtin protein. To gain insight into the pathogenesis of HD, wegenerated transgenic mice that express a cDNA encoding an N-terminalfragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Miceexpressing relatively low steady-state levels of N171 huntingtin with 82glutamine repeats (N171-82Q) develop behavioral abnormalities, includingloss of coordination, tremors, hypokinesis and abnormal gait, before dyingprematurely. In mice exhibiting these abnormalities, diffuse nuclearlabeling, intranuclear inclusions and neuritic aggregates, allimmunoreactive with an antibody to the N-terminus (amino acids 1-17) ofhuntingtin (AP194), were found in multiple populations of neurons. None ofthese behavioral or pathological phenotypes were seen in mice expressingN171-18Q. These findings are consistent with the idea that N-terminalfragments of huntingtin with a repeat expansion are toxic to neurons, andthat N-terminal fragments are prone to form both intranuclear inclusionsand neuritic aggregates.