Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

Authors: Renée R. Handley, Suzanne J. Reid, Rüdiger Bräuning, Paul Maclean, Emily Mears, Imche Fourie, Stefano Patassini, Garth J. S. Cooper, Skye R. Rudiger, Clive J. McLaughlan, Paul J. Verma, James F. Gusella, Marcy E. MacDonald, Henry J. Waldvogel, C. Simon Bawden, Richard L. M. Faull, Russell G. Snell - Proceedings of the National Academy of Sciences, PNAS 2017 cited by 108

striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.