title: HdhQ111 Mice Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation.
abstract: The HTT CAG expansion mutation causes Huntington's Disease and is associated with a wide range of cellular consequences, including altered metabolism. The mutant allele is expressed widely, in all tissues, but the striatum and cortex are especially vulnerable to its effects. To more fully understand this tissue-specificity, early in the disease process, we asked whether the metabolic impact of the mutant CAG expanded allele in heterozygous B6.HdhQ111/+ mice would be common across tissues, or whether tissues would have tissue-specific responses and whether such changes may be affected by diet. Specifically, we cross-sectionally examined steady state metabolite concentrations from a range of tissues (plasma, brown adipose tissue, cerebellum, striatum, liver, white adipose tissue), using an established liquid chromatography-mass spectrometry pipeline, from cohorts of 8 month old mutant and wild-type littermate mice that were fed one of two different high-fat diets. The differential response to diet highlighted a proportion of metabolites in all tissues, ranging from 3% (7/219) in the striatum to 12% (25/212) in white adipose tissue. By contrast, the mutant CAG-expanded allele primarily affected brain metabolites, with 14% (30/219) of metabolites significantly altered, compared to wild-type, in striatum and 11% (25/224) in the cerebellum. In general, diet and the CAG-expanded allele both elicited metabolite changes that were predominantly tissue-specific and non-overlapping, with evidence for mutation-by-diet interaction in peripheral tissues most affected by diet. Machine-learning approaches highlighted the accumulation of diverse lipid species as the most genotype-predictive metabolite changes in the striatum. Validation experiments in cell culture demonstrated that lipid accumulation was also a defining feature of mutant HdhQ111 striatal progenitor cells. Thus, metabolite-level responses to the CAG expansion mutation in vivo were tissue specific and most evident in brain, where the striatum featured signature accumulation of a set of lipids including sphingomyelin, phosphatidylcholine, cholesterol ester and triglyceride species. Importantly, in the presence of the CAG mutation, metabolite changes were unmasked in peripheral tissues by an interaction with dietary fat, implying that the design of studies to discover metabolic changes in HD mutation carriers should include metabolic perturbations.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States of America; Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, Washington, United States of America.
authors: Jeffrey B
authors: JB
authors: Carroll
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Amy
authors: A
authors: Deik
authors: Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States of America; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Elisa
authors: E
authors: Fossale
authors: Behavioral Neuroscience Program, Department of Psychology, Western Washington University, Bellingham, Washington, United States of America.
authors: Rory M
authors: RM
authors: Weston
authors: Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Jolene R
authors: JR
authors: Guide
authors: CHDI Foundation, Inc., Princeton, New Jersey, United States of America.
authors: Jamshid
authors: J
authors: Arjomand
authors: CHDI Foundation, Inc., Princeton, New Jersey, United States of America.
authors: Seung
authors: S
authors: Kwak
authors: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Clary B
authors: CB
authors: Clish
authors: Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States of America; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Marcy E
authors: ME
authors: MacDonald
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000483:Alleles; D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D000069550:Machine Learning; D055442:Metabolome; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D019680:Trinucleotide Repeat Expansion
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins