Paradoxical delay in the onset of disease caused by super-long CAG repeat expansions in R6/2 mice.
Huntington's disease (HD) is caused by an expanded CAG repeat in the HD gene. The pathological threshold for expansion in HD is around 36 CAG repeats, although 'super-long' expansions are found in brains of HD patients. We examined the effect of varying the CAG repeat length (from 170 to 450) on behavior and neuropathology of R6/2 mice. Unexpectedly, we found that increasing the repeat length delayed onset of disease and prolonged survival, from around 4 months to over 18 months in mice with the longest repeats. The delay in onset correlated with a delayed appearance of neuronal intranuclear inclusions (NIIs). However, super-long CAG repeats are not neuroprotective. Mice carrying 2 copies of the mutant transgene die earlier than those carrying a single copy. Furthermore, neurodegeneration is present in super-long repeat length mice at mid-stage disease, whereas little neurodegeneration is seen in mice with shorter CAG repeats until end stage. Expanding the CAG repeat beyond the range where NII formation is the dominant pathology has unmasked a slowly progressing neurological phenotype in R6/2 mice with brain pathology, including the identification of a novel form of inclusion, that more closely resembles that seen in adult onset cases of HD. This mouse may represent a better model for adult-onset HD than R6/2 mice with shorter repeats.
Morton
A Jennifer
AJ
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK. ajm41@cam.ac.uk
Glynn
Dervila
D
Leavens
Wendy
W
Zheng
Zhiguang
Z
Faull
Richard L M
RL
Skepper
Jeremy N
JN
Wight
James M
JM
D017668:Age of Onset; D000375:Aging; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D018450:Disease Progression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D045586:Intranuclear Inclusion Bodies / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D004856:Postural Balance; D015996:Survival Rate; D019680:Trinucleotide Repeat Expansion
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins