Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease

Abstract

A number of mouse models expressing mutant huntingtin (htt) with an expanded polyglutamine (polyQ) domain are useful for studying the pathogenesis of Huntington's disease (HD) and identifying appropriate therapies. However, these models exhibit neurological phenotypes that differ in their severity and nature. Understanding how transgenic htt leads to variable neuropathology in animal models would shed light on the pathogenesis of HD and help us to choose HD models for investigation. By comparing the expression of mutant htt at the transcriptional and protein levels in transgenic mice expressing N-terminal or full-length mutant htt, we found that the accumulation and aggregation of mutant htt in the brain is determined by htt context. HD mouse models demonstrating more severe phenotypes show earlier accumulation of N-terminal mutant htt fragments, which leads to the formation of htt aggregates that are primarily present in neuronal nuclei and processes, as well as glial cells. Similarly, transgenic monkeys expressing exon-1 htt with a 147-glutamine repeat (147Q) died early and showed abundant neuropil aggregates in swelling neuronal processes. Fractionation of HD150Q knock-in mice brains revealed an age-dependent accumulation of N-terminal mutant htt fragments in the nucleus and synaptosomes, and this accumulation was most pronounced in the striatum due to decreased proteasomal activity. Our findings suggest that the neuropathological phenotypes of HD stem largely from the accumulation of N-terminal mutant htt fragments and that this accumulation is determined by htt context and cell-type-dependent clearance of mutant htt.

Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients

“…We previously reported a similar phenomenon in peripheral leukocytes and demonstrated the presence of N-terminal mHTT fragments in these cells, suggesting that progressive accumulation of N-terminal mHTT fragments could underlie the increase (10). N-terminal fragments are known to accumulate in neurons as part of the neuropathology in animal models (21), and it could be that this accumulation leads to increased cell death, elevating mHTT concentration in the CSF as the disease progresses. The linear associations with tau and NFL concentrations suggest that mHTT may be an indicator of overall dysfunction and/or death of mHTT-containing cells.…”

Animal models of neurodegenerative diseases

“…101 The 103 In general, HD mouse models displaying more severe phenotypes show earlier accumulation of HTT aggregates and premature neuronal death. 104 YAC128, BACHD, and Knock-in HD mice with expanded polyglutamine repeats from 97 to 150 polyglutamines display obvious HTT aggregates only at older ages and have a lifespan similar to wild-type mice. 90,91,93 BACHD mice exhibit pronounced striatal and cortical atrophy, and neurodegeneration at the age of 12 months.…”

“…Hdh Q150/Q150 and Hdh Q111/Q111 mice exhibit neuronal intranuclear inclusions predominantly in the striatum, but only at older ages, such as from 15 to 22 months. 93,102,104 Thus, although knock-in HD mouse models accurately replicate the underlying genetic defect of HD, they do not display the robust motor deficit and neuronal cell loss observed in HD patients. In that sense, BACHD and YAC128 could be regarded as better models for drug testing.…”

Oligonucleotide therapeutic approaches for Huntington disease

“…Mutant huntingtin shares these sites of proteolysis (45,47). It is unclear if differences in cleavage rates contribute to toxicity of mutant huntingtin fragments through changes in folding, clearance of mutant huntingtin fragments, or the propensity for mutant huntingtin (and fragments) to aggregate or form aberrant protein interactions (48)(49)(50). Thus, combinatorial changes by the mutant huntingtin and its fragments might underlie complexities in HD pathogenesis.…”