Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT.
Huntington's disease (HD) is a fatal neurodegenerative disease characterized by metabolic, cognitive, and motor deficits. HD is caused by an expanded CAG repeat in the first exon of the HTT gene, resulting in an expanded polyglutamine section. Dietary restriction (DR) increases lifespan and ameliorates age-related pathologies, including in a model of HD, but the mechanisms mediating these protective effects are unknown. We report metabolic and behavioral effects of DR in the full-length YAC128 HD mouse model, and associated transcriptional changes in hypothalamus and striatum. DR corrected many effects of the transgene including increased body weight, decreased blood glucose, and impaired motor function. These changes were associated with reduced striatal human (but not mouse) HTT expression, as well as alteration in gene expression regulating histone acetylation modifications, particularly Hdac2. Other mRNAs related to Huntington's pathology in striatal tissue showed significant modulation by the transgene, dietary restriction or both. These results establish a protective role of DR in a transgenic model that contains the complete human HTT gene and for the first time suggest a role for DR in lowering HTT level, which correlates with severity of symptoms.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, New York, NY 10029, USA. Electronic address: Cesar.moreno@mssm.edu.
Cesar L
CL
Moreno
Friedman Brain Institute, New York, NY 10029, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: Michelle.ehrlich@mssm.edu.
Michelle E
ME
Ehrlich
Friedman Brain Institute, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: Charles.mobbs@mssm.edu.
Charles V
CV
Mobbs
D000107:Acetylation; D000818:Animals; D001786:Blood Glucose / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D005215:Fasting / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
D001786:Blood Glucose; C086055:HTT protein, human; D006657:Histones; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2
Creb-binding protein; Dietary restriction; HDAC; HTT; Huntington's disease; NF-κB; YAC128