Abstract
Huntington's disease (HD) is a neurodegenerative disorder characterized by a progressive motor and cognitive decline and the development of psychiatric symptoms. The origin of molecular and biochemical disturbances in HD is a mutation in the HTT gene, which is autosomally dominantly inherited. The altered huntingtin protein is ubiquitously expressed in the CNS, as well as in peripheral tissues. In this study we measured the metabolism changes in gene transcription in blood of HD gene carriers (premanifest and manifest combined) versus 28 healthy controls. The comparison revealed statistically significant Global Pattern Recognition Fold Change (FC) for 6 mRNA transcripts, reflecting an increase of: MAOB (FC = 3.07; p = 0.0005) which encodes an outer mitochondrial membrane-bound enzyme called monoamine oxidase type B; TGM2 (FC = 1.8; p = 0.02) encoding a transglutaminase 2 that mediates cellular stress; SLC2A4 (FC = 1.64; p = 0.02) solute carrier family 2 (facilitated glucose transporter) member 4; branched chain ketoacid dehydrogenase kinase (BCKDK) (FC = 1.34; p = 0.02); decrease of LDHA (FC = -1.16; p = 0.03) lactate dehydrogenase A; and brain-derived neurotrophic factor (BDNF) (FC = -2,11; p = 0.03). These distinguished changes coincided with HD progress. The analyses of gene transcription levels in sub-cohorts confirmed these changes and also revealed 28 statistically significant FCs of gene transcripts involved in ATP production and BCAA metabolism.
Highlights
Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder with no effective treatment (The Huntington’s Disease Collaborative Research Group 1993; Perez-De La Cruz and Santamaria 2007)
In this study we focused on energy metabolism pathways in blood cells in order to evaluate energy metabolism changes at the gene transcription level, using quantitative
Β2 fraction levels, alfa-1 globulins level and FT3 level were significantly different between the control group (CG) and HDG, but were within the range of reference values
Summary
Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder with no effective treatment (The Huntington’s Disease Collaborative Research Group 1993; Perez-De La Cruz and Santamaria 2007). The unchanged polyQ tract is an active point of HTT in binding to other protein partners, but an elongated polyQ tract leads to the formation of nuclear and cytoplasmic aggregates, confers a gain-of-function as well as a loss-of-function of huntingtin and causes pathological changes on the cellular level inside and outside the CNS (Bjorkqvist et al 2008; Sathasivam et al 1999). Both the number of CAG repeats in the larger allele and epigenetic factors contribute to HD onset age and disease progression.
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