Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis

PLoS Genet. 2017 Jul 17;13(7):e1006846. doi: 10.1371/journal.pgen.1006846. eCollection 2017 Jul.

Abstract

Huntington's Disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by cognitive, behavioral and motor dysfunctions. HD is caused by a CAG repeat expansion in exon 1 of the HD gene that is translated into an expanded polyglutamine tract in the encoded protein, huntingtin (HTT). While the most significant neuropathology of HD occurs in the striatum, other brain regions are also affected and play an important role in HD pathology. To date there is no cure for HD, and recently strategies aiming at silencing HTT expression have been initiated as possible therapeutics for HD. However, the essential functions of HTT in the adult brain are currently unknown and hence the consequence of sustained suppression of HTT expression is unpredictable and can potentially be deleterious. Using the Cre-loxP system of recombination, we conditionally inactivated the mouse HD gene homologue at 3, 6 and 9 months of age. Here we show that elimination of Htt expression in the adult mouse results in behavioral deficits, progressive neuropathological changes including bilateral thalamic calcification, and altered brain iron homeostasis.

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain / metabolism
  • Brain / physiopathology*
  • Brain Diseases / genetics
  • Brain Diseases / pathology
  • Calcinosis / diagnosis
  • Calcinosis / genetics*
  • Calcinosis / pathology
  • Disease Models, Animal
  • Exons
  • Female
  • Gene Expression Regulation
  • Genotyping Techniques
  • Gliosis / diagnosis
  • Gliosis / genetics
  • Homeostasis
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics*
  • Iron / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Ribosomal, 18S / genetics

Substances

  • Huntingtin Protein
  • RNA, Ribosomal, 18S
  • Iron

Grants and funding

This work was supported by CHDI Foundation, Inc. (http://chdifoundation.org/) grant numbers A-1589 and A-5423 to ID and with generous support from CO-ED for a CURE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.