title: Regulation of feedback between protein kinase A and the proteasome system worsens Huntington's disease.
abstract: Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6(S120A)) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6(S120D)) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan.
authors.forename: Jiun-Tsai
authors.initials: JT
authors.lastname: Lin
authors.forename: Wei-Cheng
authors.initials: WC
authors.lastname: Chang
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.forename: Hsing-Lin
authors.initials: HL
authors.lastname: Lai
authors.forename: Chih-Yeh
authors.initials: CY
authors.lastname: Chen
authors.forename: Mi-Hua
authors.initials: MH
authors.lastname: Tao
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D000818:Animals; D002460:Cell Line; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009043:Motor Activity; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats
chemical_list: C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D046988:Proteasome Endopeptidase Complex