Dysregulation of C/EBPα by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBPalpha, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBPalpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPalpha into aggregates, as well as suppressed expression of the C/EBPalpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPalpha's activity, and repair of the urea cycle deficiency and hyperammonemia, but also ameliorated the formation of Htt aggregates, the motor deterioration, the suppression of striatal brain-derived neurotrophic factor and the normalization of three protein chaperones (Hsp27, Hsp70 and Hsp90). Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD.

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

“…They also identified elevated blood citrulline and arginine, supporting systemic involvement of a urea cycle defect in HD. Increased blood citrulline has previously been described in HD cases and mouse models of HD (13,46). Chiang et al (13) first suggested the dysfunction of cellular processes in the liver as a pathogenic mechanism in HD, when they reported reduced activity of the urea cycle enzymes arginosuccinate-lyase, arginosuccinate synthase, and arginase in the liver of R6/2 mice, as well as hyperammonemia.…”

“…Increased blood citrulline has previously been described in HD cases and mouse models of HD (13,46). Chiang et al (13) first suggested the dysfunction of cellular processes in the liver as a pathogenic mechanism in HD, when they reported reduced activity of the urea cycle enzymes arginosuccinate-lyase, arginosuccinate synthase, and arginase in the liver of R6/2 mice, as well as hyperammonemia. As seen in UCDs, the hyperammonemia and symptom profile of these mice improved when they were treated with a low-protein diet (13).…”

“…Chiang et al (13) first suggested the dysfunction of cellular processes in the liver as a pathogenic mechanism in HD, when they reported reduced activity of the urea cycle enzymes arginosuccinate-lyase, arginosuccinate synthase, and arginase in the liver of R6/2 mice, as well as hyperammonemia. As seen in UCDs, the hyperammonemia and symptom profile of these mice improved when they were treated with a low-protein diet (13). Further studies now also support HD as a systemic disease, including a breath test showing dysfunction of liver mitochondria in prodromal HD patients.…”

“…Circulating levels of branched chain amino acids are reduced in HD individuals, and this decline correlates with weight loss (11). Levels of citrulline were also reportedly elevated in blood from HD individuals (13), indicating a potential role of the urea cycle, a critical pathway for clearing ammonia generated through protein catabolism. Within the CNS, a recent study found altered levels of amino acids in multiple regions of the postmortem HD brain as well as increased concentrations of glucose, sorbitol, fructose, and urea (14).…”

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…The brains of HD animal models, however, show a decrease in HSP70 and its cochaperone HSP40 (Hay et al, 2004;Chiang et al, 2007;Duan et al, 2008;Yamanaka et al, 2008), which have been found to colocalize with Htt aggregates (Jana et al, 2000). Of significance, in cultured neurons and rats subjected to cerebral ischemia, after treatment with either lithium or VPA, expression of HSP70 was found to increase (Ren et al, 2003Kim et al, 2007;Marinova et al, 2009Marinova et al, , 2011.…”