title: Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative.
abstract: Huntington's disease (HD) involves marked early neurodegeneration in the striatum, whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in the striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between the striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Fossale
authors.forename: Ihn Sik
authors.initials: IS
authors.lastname: Seong
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Coser
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D000067696:Ataxin-1; D000067528:Ataxins; D015415:Biomarkers / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D015415:Biomarkers; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse