Longitudinal behavioral, cross-sectional transcriptional and histopathological characterization of a knock-in mouse model of Huntington's disease with 140 CAG repeats

Abstract

The discovery of the gene mutation responsible for Huntington's Disease (HD), huntingtin, in 1993 allowed for a better understanding of the pathology of the and enabled development of animal models. HD is caused by the expansion of a polyglutamine repeat region in the N-terminal of the huntingtin protein. Here we examine the behavioral, transcriptional, histopathological and anatomical characteristics of a knock-in HD mouse model with a 140 polyglutamine expansion in the huntingtin protein. This CAG 140 model contains a portion of the human exon 1 with 140 CAG repeats knocked into the mouse huntingtin gene. We have longitudinally examined the rearing behavior, accelerating rotarod, constant speed rotarod and gait for the heterozygote, homozygote and their non-transgenic littermates and have found a significant difference in the afflicted mice. However, while there were significant differences between the non-transgenic and the knock-in mice, these behaviors were not progressive. As in HD, we show that the CAG 140 mice also have a significant decrease in striatally enriched mRNA transcripts. In addition, striatal neuronal intranuclear inclusion density increases with age. Lastly these CAG 140 mice show slight cortical thinning compared to unaffected littermates, similarly to the cortical thinning recently reported in HD.

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

“…D2GFP decline progresses through 31 wk of age before plateauing at ∼62% of wild type. This D2GFP loss is before the reported rotarod latency deficit, and is also before the age at which reliable detection of Drd2 loss by in situ hybridization is reported (27). Before plateauing, this strain demonstrates greater variance at the younger ages tested.…”

Transcriptional modulator H2A histone family, member Y ( H2AFY ) marks Huntington disease activity in man and mouse

“…By contrast to florid mouse models carrying an N-terminal huntingtin fragment (e.g., R6/2 mice), mice carrying a chimeric mouse/human exon 1 containing 140 CAG repeats inserted in the murine huntingtin gene more faithfully model the disease genetics and have normal life spans (26,27), and they develop a subtle pathologic phenotype that is most analogous to presymptomatic and early symptomatic stages of the human disease (26). Despite a mild phenotype, knock-in mice have abnormal motor behavior that can be quantified by formal behavioral testing and aged mice show characteristic striatal nuclear huntingtin aggregates (26,27) as well as ∼20% underexpression of select striatal enriched transcripts [e.g., D2 receptor and dopamine-and cAMP-regulated neuronal phosphoprotein (DARPP-32)] (27) in the absence of neuronal cell loss.…”

“…Despite a mild phenotype, knock-in mice have abnormal motor behavior that can be quantified by formal behavioral testing and aged mice show characteristic striatal nuclear huntingtin aggregates (26,27) as well as ∼20% underexpression of select striatal enriched transcripts [e.g., D2 receptor and dopamine-and cAMP-regulated neuronal phosphoprotein (DARPP-32)] (27) in the absence of neuronal cell loss. To validate our findings in this full-length huntingtin knock-in model, we assayed macroH2A1 levels in histone extracts from the striatum of homozygous 140-CAG knock-in mice compared with age-and sex-matched wildtype mice.…”

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: 18F-MNI-659 and 18F-MNI-654

“…PDE10A is therefore an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function (9), including Parkinson disease (10), Huntington disease (11,12), schizophrenia (13,14), memory disorders (15), depression, and addiction (16). Animal models of Huntington disease have shown that PDE10A expression is an extremely sensitive marker of striatal neuron loss (12,17), and Parkinson disease models have been used to demonstrate possible roles of PDE10A in both the early motor symptoms and the late complications of Parkinson disease due to prominent PDE10A-dependent dysregulation of corticostriatal signaling (10,18). Developing imaging agents to accurately and sensitively interrogate PDE10A in vivo would greatly help in understanding changes in PDE10A in human brain disorders and speed the development of potential therapeutics targeting this enzyme.…”