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]

Abstract

Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1-17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.

Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease

“…Sequestration of mTOR to aggregates was associated with reduced amounts of soluble mTOR (relative to tubulin) in stable inducible cell lines expressing mutant versus wild-type huntingtin (Figs. 1d and 2a) and in brain lysates of mice expressing mutant huntingtin 16 (Fig. 2b) versus control littermates.…”

“…Sequestration of mTOR was not an artefact of protein overexpression or aggregation, as we found no colocalization of certain upstream mTOR regulators or unrelated proteins (Akt, Pdk1, Pten) with mutant huntingtin aggregates (data not shown). mTOR was also sequestered in huntingtin aggregates in brains of transgenic mice expressing N-terminal mutant huntingtin fragments 16 (Fig. 1b) and of individuals with Huntington disease (Fig.…”

“…We observed these phenomena in mutant PC12 cells at times where cell death was negligible 20 , and cell death was not obvious in the mice expressing mutant huntingtin that we studied 16 . In addition, we observed sequestration of mTOR to mutant huntingtin aggregates in association with decreased S6 phosphorylation and increased autophagy in aggregatecontaining cells with nonapoptotic nuclear morphologies and in cells treated with the pan-caspase inhibitor z-VAD-fmk ( Supplementary Figs.…”

“…12 online) and then used it to treat mice expressing mutant huntingtin. We used Ross/Borchelt mice expressing mutant huntingtin 16 maneuver test and tremors 36 . Ross/Borchelt mice treated with CCI-779 performed significantly better on each of these tasks than their Ross/Borchelt littermates treated with a placebo (Fig.…”

Mouse models of Huntington's disease

“…The R6/1 and R6/2 lines, which express mutant human exon 1 HTT, were the first transgenic lines produced (Mangiarini et al, 1996) and the R6/2 mouse has been the most extensively studied and utilized mouse model of HD to date. Another N-terminal transgenic mouse is the N171-82Q line (Schilling et al, 1999) expressing a 171 amino acid mutant HTT fragment under the regulation of the mouse prion promoter, which directs expression primarily in the brain. These and other N-terminal transgenics are available from The Jackson Laboratory (JAX) and/or CHDI Foundation (Table 1).…”