Huntingtin inclusions do not down-regulate specific genes in the R6/2 Huntington's disease mouse.
Transcriptional dysregulation is a central pathogenic mechanism in Huntington's disease (HD); HD and transgenic mouse models of HD demonstrate down-regulation of specific genes at the level of mRNA expression. Furthermore, neuronal intranuclear inclusions (NIIs) have been identified in the brains of R6/2 mice and HD patients. One possibility is that NIIs contribute to transcriptional dysregulation by sequestering transcription factors. We therefore assessed the relationship between NIIs and transcriptional dysregulation in the R6/2 mouse, using double-label in situ hybridization combined with immunohistochemistry, and laser capture microdissection combined with quantitative real-time PCR. There was no difference in transcript levels of specific genes between NII-positive and NII-negative neurons. These results demonstrate that NIIs do not cause decreases in D2, PPE and PSS mRNA levels in R6/2 striatum and therefore are not involved in the down-regulation of these specific genes in this HD model. In addition, these observations argue against the notion that NIIs protect against transcriptional dysregulation in HD.
Sadri-Vakili
G
G
Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street/B114- 2001, Charlestown, MA 02129-4404, USA.
Menon
A S
AS
Farrell
L A
LA
Keller-McGandy
C E
CE
Cantuti-Castelvetri
I
I
Standaert
D G
DG
Augood
S J
SJ
Yohrling
G J
GJ
Cha
J-H J
JH
D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism
D004745:Enkephalins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; D017448:Receptors, Dopamine D2; D013004:Somatostatin; C033660:preproenkephalin