A study of molecular changes relating to energy metabolism and cellular stress in people with Huntington's disease:...

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.