Early Motor Dysfunction and Striosomal Distribution of Huntingtin Microaggregates in Huntington's Disease Knock-In Mice

Abstract

Huntington's disease (HD) is characterized by a progressive loss of neurons in the striatum and cerebral cortex and is caused by a CAG repeat expansion in the gene encoding huntingtin. Mice with the mutation inserted into their own huntingtin gene (knock-in mice) are, genetically, the best models of the human disease. Here we show for the first time that knock-in mice with 94 CAG repeats develop a robust and early motor phenotype at 2 months of age, characterized by increased rearing at night. This initial increase in repetitive movements was followed by decreased locomotion at 4 and 6 months, despite a normal life span. The decrease in striatal enkephalin mRNA that is known to occur at 4 months was not present at 2 months, when increased rearing was observed. Both the hyperactive and hypoactive phases of motor dysfunction preceded the detection of nuclear microaggregates of mutated huntingtin in striatal neurons. Nuclear microaggregates, defined as small huntingtin-positive punctas detected by light microscopy, were very rare at 4 months but became widely distributed in striatal neurons at 6 months. Nuclear inclusions did not appear until 18 months. When present, nuclear microaggregates predominated in the striosomal compartment of the striatum, providing a possible explanation for the different neuronal vulnerability of striatal compartments observed in humans. The early motor phenotype observed in the knock-in mouse is reminiscent of repetitive movements often observed in early HD and provides a novel opportunity to assess the ability of therapies to prevent the initial effects of the mutation in vivo.

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

“…On the other hand, calbindin is decreased in PCs but not in the striatum [25]. 2) In several HD mouse models with ubiquitous transgene expression, inclusion formation and/or cell loss is preponderant in the striatum, and sometimes even MSN-subtype specific [31][32][33]. These data confirm that HD mouse models replicate the human pattern of neuronal disease.…”

Animal models of neurodegenerative diseases

“…These models include transgenic mice, such as R6/2 and N171-82Q, expressing the amino-terminal region of human mutant HTT [87][88][89] ; transgenic mice, such as yeast artificial chromosome mice (YAC128) and bacterial artificial chromosome mice (BACHD), expressing full-length human mutant HTT 90,91 ; and knock-in mice, such as Hdh , generated by replacing the first exon of the murine HTT gene by the first exon of the human HTT gene containing expanded CAG repeats. [92][93][94] R6/2 mice display a robust phenotype, including motor deficits, such as lack of motor coordination, abnormal gait and hypoactivity, and learning impairment, with age of onset of about four weeks. 89,95,96 Aggregate formation is very pronounced in R6/2 mice, with intranuclear inclusions similar to those observed in biopsy material from HD patients and occurring prior to the development of symptoms.…”

Computational Investigations of Cognitive Impairment in Huntington's Disease

“…Animal studies with knock-in mice have verified the two-stage neurodegenerative process that starts with hyperkinesia and continues with hypokinesia, mirroring the progression of cell death from predominantly D2-receptor MSNs associated with the indirect pathway followed by the D1-receptor MSNs that are associated with the direct pathway (Menalled et al, 2002).…”