Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington's disease knock-in mice

• Type of Material: Article
• Authors: Liliana B. Menalled, University of California, Los Angeles; Jessica D. Sison, University of California, Los Angeles; Ying Wu, University of California, Los Angeles; Melisa Olivieri, University of California, Los Angeles; Xiao-Jiang Li, Emory University; He Li, Emory University; Scott Zeitlin, University of Virginia; Marie-Francoise Chesselet, University of California, Los Angeles
• Language: English
• Date: 2002-09-15
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2002 Society for Neuroscience
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.22-18-08266.2002
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 22
• Issue: 18
• Start Page: 8266
• End Page: 8276
• Grant/Funding Information: This work was supported by the Hereditary Disease Foundation's Cure HD Initiative.
• Keywords: Science & Technology; microaggregates; NEURONAL INTRANUCLEAR INCLUSIONS; striosomes; mouse; behavior; Huntington's disease; CAG repeats; MUTANT HUNTINGTIN; CAG EXPANSION; mu-opioid receptor; nuclear inclusions; PROGRESSIVE FORMATION; knock-in; ASPARTATE RECEPTOR ACTIVATION; immunohistochemistry; Neurosciences & Neurology; striatum; Life Sciences & Biomedicine; BASAL GANGLIA; NUCLEAR-LOCALIZATION; STRIATAL NEURONS; Neurosciences; HD TRANSGENIC MICE; BEHAVIORAL ABNORMALITIES
• Research Categories: Biology, Neuroscience; Biology, Genetics

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 prededed 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.