PMID- 24728190
OWN - NLM
STAT- MEDLINE
DCOM- 20150330
LR  - 20140804
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 23
IP  - 17
DP  - 2014 Sep 1
TI  - Progressive axonal transport and synaptic protein changes correlate with 
      behavioral and neuropathological abnormalities in the heterozygous Q175 KI mouse 
      model of Huntington's disease.
PG  - 4510-27
LID - 10.1093/hmg/ddu166 [doi]
AB  - A long-term goal of modeling Huntington's disease (HD) is to recapitulate the 
      cardinal features of the disease in mice that express both mutant and wild-type 
      (WT) huntingtin (Htt), as HD commonly manifests as a heterozygous condition in 
      humans, and loss of WT Htt is associated with loss-of-function. In a new 
      heterozygous Q175 knock-in (KI) mouse model, we performed an extensive evaluation 
      of motor and cognitive functional deficits, neuropathological and biochemical 
      changes and levels of proteins involved in synaptic function, the cytoskeleton 
      and axonal transport, at 1-16 months of age. Motor deficits were apparent at 6 
      months of age in Q175 KI mice and at that time, postmortem striatal 
      gamma-aminobutyric acid (GABA) levels were elevated and mutant Htt inclusions 
      were present throughout the brain. From 6 months of age, levels of proteins 
      associated with synaptic function, including SNAP-25, Rab3A and PSD-95, and with 
      axonal transport and microtubules, including KIF3A, dynein and dynactin, were 
      altered in the striatum, motor cortex, prefrontal cortex and hippocampus of Q175 
      KI mice, compared with WT levels. At 12-16 months of age, Q175 KI mice displayed 
      motor and cognitive deficits, which were paralleled at postmortem by striatal 
      atrophy, cortical thinning, degeneration of medium spiny neurons, dense mutant 
      Htt inclusion formation, decreased striatal dopamine levels and loss of striatal 
      brain-derived neurotrophic factor (BDNF). Data from this study indicate that the 
      heterozygous Q175 KI mouse represents a realistic model for HD and also provides 
      new insights into the specific and progressive synaptic, cytoskeletal and axonal 
      transport protein abnormalities that may accompany the disease.
CI  - (c) The Author 2014. Published by Oxford University Press. All rights reserved. For 
      Permissions, please email: journals.permissions@oup.com.
FAU - Smith, Gaynor A
AU  - Smith GA
AD  - McLean Hospital/Harvard Medical School, Neuroregeneration Research Institute and 
      Laboratories, Belmont, MA, USA.
FAU - Rocha, Emily M
AU  - Rocha EM
AD  - McLean Hospital/Harvard Medical School, Neuroregeneration Research Institute and 
      Laboratories, Belmont, MA, USA.
FAU - McLean, Jesse R
AU  - McLean JR
AD  - McLean Hospital/Harvard Medical School, Neuroregeneration Research Institute and 
      Laboratories, Belmont, MA, USA.
FAU - Hayes, Melissa A
AU  - Hayes MA
AD  - McLean Hospital/Harvard Medical School, Neuroregeneration Research Institute and 
      Laboratories, Belmont, MA, USA.
FAU - Izen, Sarah C
AU  - Izen SC
AD  - McLean Hospital/Harvard Medical School, Neuroregeneration Research Institute and 
      Laboratories, Belmont, MA, USA.
FAU - Isacson, Ole
AU  - Isacson O
AD  - McLean Hospital/Harvard Medical School, Neuroregeneration Research Institute and 
      Laboratories, Belmont, MA, USA.
FAU - Hallett, Penelope J
AU  - Hallett PJ
AD  - McLean Hospital/Harvard Medical School, Neuroregeneration Research Institute and 
      Laboratories, Belmont, MA, USA phallett@mclean.harvard.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140412
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 0 (Slc6a4 protein, mouse)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Aging/pathology
MH  - Animals
MH  - Atrophy/genetics/pathology
MH  - *Axonal Transport
MH  - *Behavior, Animal
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cytoskeleton/metabolism
MH  - Disease Models, Animal
MH  - Gene Knock-In Techniques
MH  - Heterozygote
MH  - Huntington Disease/*genetics/*pathology
MH  - Inclusion Bodies/metabolism
MH  - Metabolome
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mutation/genetics
MH  - Neostriatum/metabolism/pathology
MH  - Neurotransmitter Agents/metabolism
MH  - Receptor, trkB/metabolism
MH  - Serotonin Plasma Membrane Transport Proteins/metabolism
MH  - Synapses/*metabolism
EDAT- 2014/04/15 06:00
MHDA- 2015/03/31 06:00
CRDT- 2014/04/15 06:00
PHST- 2014/04/15 06:00 [entrez]
PHST- 2014/04/15 06:00 [pubmed]
PHST- 2015/03/31 06:00 [medline]
AID - ddu166 [pii]
AID - 10.1093/hmg/ddu166 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2014 Sep 1;23(17):4510-27. doi: 10.1093/hmg/ddu166. Epub 2014 Apr 
      12.