UNASSIGNED: The HTT CAG expansion mutation causes @entity2033 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/+ @entity19 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 @entity19 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 @entity4291 , @entity2434 , @entity14839 and @entity412 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 @entity2033 mutation carriers should include metabolic perturbations.

HdhQ111 XXXX Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation.

@entity14839 :: ('CHEBI:17002', 'Chemical') :: ['cholesterol ester'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity2434 :: ('MESH:D010713', 'Chemical') :: ['phosphatidylcholine'] @entity2033 :: ('MESH:D006816', 'Disease') :: ["Huntington's Disease", 'HD'] @entity412 :: ('CHEBI:17855', 'Chemical') :: ['triglyceride'] @entity4291 :: ('CHEBI:17636', 'Chemical') :: ['sphingomyelin']
@entity19 :: (10090,Species) :: ['Mice']
