title: Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease.
abstract: Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by aberrant expansion of the polyQ tract in Huntingtin (HTT). While motor impairment mediated by polyQ-expanded HTT has been intensively studied, molecular mechanisms for nonmotor symptoms in HD, such as psychiatric manifestations, remain elusive. Here we have demonstrated that HTT forms a ternary protein complex with the scaffolding protein DISC1 and cAMP-degrading phosphodiesterase 4 (PDE4) to regulate PDE4 activity. We observed pathological cross-seeding between DISC1 and mutant HTT aggregates in the brains of HD patients as well as in a murine model that recapitulates the polyQ pathology of HD (R6/2 mice). In R6/2 mice, consequent reductions in soluble DISC1 led to dysregulation of DISC1-PDE4 complexes, aberrantly increasing the activity of PDE4. Importantly, exogenous expression of a modified DISC1, which binds to PDE4 but not mutant HTT, normalized PDE4 activity and ameliorated anhedonia in the R6/2 mice. We propose that cross-seeding of mutant HTT and DISC1 and the resultant changes in PDE4 activity may underlie the pathology of a specific subset of mental manifestations of HD, which may provide an insight into molecular signaling in mental illness in general.
authors.forename: Motomasa
authors.initials: M
authors.lastname: Tanaka
authors.forename: Koko
authors.initials: K
authors.lastname: Ishizuka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nekooki-Machida
authors.forename: Ryo
authors.initials: R
authors.lastname: Endo
authors.forename: Noriko
authors.initials: N
authors.lastname: Takashima
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Komi
authors.forename: Amy
authors.initials: A
authors.lastname: Gathercole
authors.forename: Elaine
authors.initials: E
authors.lastname: Huston
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Kelvin Kai-Wan
authors.initials: KK
authors.lastname: Hui
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.forename: Sun-Hong
authors.initials: SH
authors.lastname: Kim
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
mesh_terms: D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000201:enzymology*; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000201:enzymology*
chemical_list: C412476:DISC1 protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human