Effects of partial suppression of parkin on huntingtin mutant R6/1 mice.
Huntington's disease (HD) is a neurodegenerative disorder caused by an expansion of polyglutamines which makes huntingtin more resistant to degradation. Parkin is an ubiquitin ligase which promotes proteosomal degradation of abnormal proteins. We investigated whether partial suppression of parkin increases HD phenotype. We studied the behavior and brain histology and biochemistry of the mice produced by interbreeding of R6/1 (model of HD in mice) with Park-2(-/-) (parkin null mice): R6/1, WT (wild-type), PK(+/-) (hemizygotic deletion of Park-2) and R6/1/PK(+/-). R6/1 and R6/1/PK(+/-) mice had abnormal motor and exploratory behavior. R6/1/PK(+/-) mice were more akinetic. These two groups of mice had severe but similar loss of nigrostriatal dopamine neurons and monoamine levels in striatum. R6/1/PK(+/-) mice had fewer huntingtin inclusions and a greater number of TUNEL(+) cells than R6/1 in striatum but there were no differences in the hippocampus. DARPP-32 protein was equally reduced in striatum of R6/1 and R6/1/PK(+/-) mice. Striatal levels of GSH were increased, of HSP-70 reduced and of CHIP unchanged in both R6/1 and R6/1/PK(+/-) mice. LC-3 II/I ratios were significantly increased in striatum of R6/1/PK(+/-) mice. Partial suppression of parkin slightly aggravates the phenotype in R6/1 mice, confirming a pathogenic role of the UPS in the processing of mutant huntingtin. The absence of massive additional cellular lesions in R6/1/PK(+/-) mice suggests the existence of compensatory mechanisms, such as autophagy, for the processing of huntingtin.
Rubio
Isabel
I
Servicio de Neurología, Hospital Ramón y Cajal, Madrid, Spain.
Rodríguez-Navarro
José Antonio
JA
Tomás-Zapico
Cristina
C
Ruíz
Carolina
C
Casarejos
María José
MJ
Perucho
Juan
J
Gómez
Ana
A
Rodal
Izaskun
I
Lucas
José J
JJ
Mena
María Angeles
MA
de Yébenes
Justo García
JG
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005106:Exploratory Behavior; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
D015306:Biogenic Monoamines; D018840:HSP70 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine