Novel BAC Mouse Model of Huntington's Disease with 225 CAG Repeats Exhibits an Early Widespread and Stable Degenerative Phenotype.
BACKGROUND
Unusually large CAG repeat expansions (>60) in exon one of Huntingtin (HTT) are invariably associated with a juvenile-onset form of Huntington's disease (HD), characterized by a more extensive and rapidly progressing neuropathology than the more prevalent adult-onset form. However, existing mouse models of HD that express the full-length Htt gene with CAG repeat lengths associated with juvenile HD (ranging between ~75 to ~150 repeats in published models) exhibit selective neurodegenerative phenotypes more consistent with adult-onset HD. Objective: To determine if a very large CAG repeat (>200) in full-length Htt elicits neurodegenerative phenotypes consistent with juvenile HD.


METHODS
Using a …bacterial artificial chromosome (BAC) system, we generated mice expressing full-length mouse Htt with ~225 CAG repeats under control of the mouse Htt promoter. Mice were characterized using behavioral, neuropathological, biochemical and brain imaging methods.


RESULTS
BAC-225Q mice exhibit phenotypes consistent with a subset of features seen in juvenile-onset HD: very early motor behavior abnormalities, reduced body weight, widespread and progressive increase in Htt aggregates, gliosis, and neurodegeneration. Early striatal pathology was observed, including reactive gliosis and loss of dopamine receptors, prior to detectable volume loss. HD-related blood markers of impaired energy metabolism and systemic inflammation were also increased. Aside from an age-dependent progression of diffuse nuclear aggregates at 6 months of age to abundant neuropil aggregates at 12 months of age, other pathological and motor phenotypes showed little to no progression.


CONCLUSIONS
The HD phenotypes present in animals 3 to 12 months of age make the BAC-225Q mice a unique and stable model of full-length mutant Htt associated phenotypes, including body weight loss, behavioral impairment and HD-like neurodegenerative phenotypes characteristic of juvenile-onset HD and/or late-stage adult-onset HD.
Department of Neurology, Vandeerbilt University Medical Center, Nashville, TN, USA.
Michal
M
Wegrzynowicz
Terry Jo
TJ
Bichell
Barbara D
BD
Soares
Meredith K
MK
Loth
Jennifer S
JS
McGlothan
Susumu
S
Mori
Fatima S
FS
Alikhan
Kegang
K
Hua
Jennifer M
JM
Coughlin
Hunter K
HK
Holt
Christopher S
CS
Jetter
Martin G
MG
Pomper
Alexander P
AP
Osmand
Tomás R
TR
Guilarte
Aaron B
AB
Bowman
D000818:Animals; D001284:Atrophy; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D022202:Chromosomes, Artificial, Bacterial; D004195:Disease Models, Animal; D018450:Disease Progression; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse