title: Localized changes to glycogen synthase kinase-3 and collapsin response mediator protein-2 in the Huntington's disease affected brain.
abstract: All cases of Huntington's disease (HD) are caused by mutant huntingtin protein (mhtt), yet the molecular mechanisms that link mhtt to disease symptoms are not fully elucidated. Given glycogen synthase kinase-3 (GSK3) is implicated in several neurodegenerative diseases as a molecular mediator of neuronal decline and widely touted as a therapeutic target, we investigated GSK3 in cells expressing mhtt, brains of R6/1 HD mice and post-mortem human brain samples. Consistency in data across the two models and the human brain samples indicate decreased GSK3 signalling contributes to neuronal dysfunction in HD. Inhibitory phosphorylation of GSK3 (pGSK3) was elevated in mhtt cells and this appeared related to an overall energy metabolism deficit as the mhtt cells had less ATP and inhibiting ATP production in control cells expressing non-pathogenic htt with paraquat also increased pGSK3. pGSK3 was increased and ATP levels decreased in the frontal cortex and striatum of R6/1 mice and levels of cortical pGSK3 inversely correlated with cognitive function of the mice. Consistent with decreased GSK3 activity in the R6/1 mouse brain, β-catenin levels were increased and phosphorylation of collapsin response mediator protein-2 (CRMP2) decreased in the frontal cortex where inhibitory phosphorylation of GSK3 was the greatest. pGSK3 was predominantly undetectable in HD and healthy control human brain samples, but levels of total GSK3 were decreased in the HD-affected frontal cortex and this correlated with decreased pCRMP2. Thus, disruptions to cortical GSK3 signalling, possibly due to localized energy metabolism deficits, appear to contribute to the cognitive symptoms of HD.
authors.affiliation: Department of Pathology.
authors.forename: Nastasia K H
authors.initials: NK
authors.lastname: Lim
authors.affiliation: Bio21 Institute Florey Institute of Neuroscience and Mental Health.
authors.forename: Lin W
authors.initials: LW
authors.lastname: Hung
authors.affiliation: Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Terence Y
authors.initials: TY
authors.lastname: Pang
authors.affiliation: Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia.
authors.forename: Catriona A
authors.initials: CA
authors.lastname: Mclean
authors.affiliation: Department of Pathology.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Liddell
authors.affiliation: Department of Pathology.
authors.forename: James B
authors.initials: JB
authors.lastname: Hilton
authors.affiliation: Florey Institute of Neuroscience and Mental Health.
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.affiliation: Department of Pathology Florey Institute of Neuroscience and Mental Health.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.affiliation: Florey Institute of Neuroscience and Mental Health Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
authors.affiliation: Department of Pathology Florey Institute of Neuroscience and Mental Health pjcrouch@unimelb.edu.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010269:Paraquat / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051176:beta Catenin; C095114:collapsin response mediator protein-2; D000255:Adenosine Triphosphate; D038362:Glycogen Synthase Kinase 3; D010269:Paraquat