Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice.
To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.
Gray
Michelle
M
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California 90095, USA.
Shirasaki
Dyna I
DI
Cepeda
Carlos
C
André
Véronique M
VM
Wilburn
Brian
B
Lu
Xiao-Hong
XH
Tao
Jifang
J
Yamazaki
Irene
I
Li
Shi-Hua
SH
Sun
Yi E
YE
Li
Xiao-Jiang
XJ
Levine
Michael S
MS
Yang
X William
XW
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D022202:Chromosomes, Artificial, Bacterial / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism
C086055:HTT protein, human; D006657:Histones; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine