Dopamine enhances motor and neuropathological consequences of polyglutamine expanded huntingtin.
An expansion in the CAG repeat of the IT15 (huntingtin) gene underlies the development of Huntington's disease (HD), but the basis for the specific vulnerability of dopamine-receptive striatal neurons remains unclear. To examine the potential role of the dopamine system in the emergence of pathological conditions in HD, we generated a double mutant mouse strain with both enhanced dopamine transmission and endogenous expression of a mutant huntingtin gene. This strain was generated by crossing the dopamine transporter knock-out mouse, which exhibits a 5-fold elevation in extracellular dopamine levels in the striatum and locomotor hyperactivity, to a knock-in mouse model of HD containing 92 CAG repeats. These double mutant mice exhibited an increased stereotypic activity at 6 months of age, followed by a progressive decline of their locomotor hyperactivity. Expression of the mutated huntingtin did not alter dopamine or its metabolite levels in normal or dopamine transporter knock-out mice. However, the mutant huntingtin protein aggregated much earlier and to a greater extent in the striatum and other dopaminergic brain regions in the hyperdopaminergic mouse model of HD. Furthermore, the formation of neuropil aggregates in the striatum and other regions of hyperdopaminergic HD mice was observed at 4 months of age, well before similar events occurred in normal HD mice (12 months). These findings indicate that dopamine contributes to the deleterious effects of mutated huntingtin on striatal function, and this is accompanied by enhanced formation of huntingtin aggregates.
Cyr
Michel
M
Neuroscience Research Group, University of Quebec at Trois-Rivieres, C.P. 500, Trois-Rivieres, Quebec G9A 5H7, Canada. cyrmi@uqtr.ca
Sotnikova
Tatyana D
TD
Gainetdinov
Raul R
RR
Caron
Marc G
MG
D000375:Aging; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics* / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D004298:Dopamine