Alterations in CSF Urea Occur in Late Manifest Stage Huntington Disease

ABSTRACT: Huntington Disease (HD) is a neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene, resulting in the production of mutant huntingtin proteins (mHTT). Previous research has identified urea as a key metabolite elevated in HD animal models and post-mortem tissues of HD patients. The exact timing of these elevations in urea and the molecular mechanism(s) responsible for these disturbances remain unknown. To better understand the pathophysiologic mechanisms responsible for elevations in urea in HD, we completed a global metabolomic profile of cerebrospinal fluid (CSF) from individuals who were at several stages of disease: pre-manifest (PRE), manifest (MAN), and late-manifest (LATE) HD participants compared to controls. We found approximately 500 metabolites were significantly altered in pre-manifest participants compared to controls, although no significant difference in CSF urea or urea metabolites. Interestingly, CSF urea was only significantly elevated in LATE participants compared to controls. There were no changes in the urea metabolites, citrulline, ornithine and arginine throughout disease; however, we did observe changes in acetate, creatinine, 4-acetamidobutanoate and 4-aminobutyraldehyde which are indirect modifiers of urea. Overall, our study confirms that elevations in urea do occur in HD, albeit later in disease and that these changes may reflect more central impairments to cellular energy metabolism yet to be explored.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Huntingtons Disease

SUBMITTER: SIMONA CODREANU  

PROVIDER: ST002442 | MetabolomicsWorkbench | Thu Jan 12 00:00:00 GMT 2023

REPOSITORIES: MetabolomicsWorkbench