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

Abstract

The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 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.is a dominantly inherited neurological disorder typified by chorea, psychological disturbance, and dementia. The symptoms progress and result in premature death, typically 10-15 y after onset. Currently no available treatment can delay or prevent the onset of HD. The gene responsible, Huntingtin (HTT), is ubiquitously expressed and encodes the large and multifunctional huntingtin protein.The disease-causing mutation is an expanded CAG repeat in exon 1 of HTT, coding for a glutamine tract within the protein (1). The disease-causing repeat lower length threshold is 36 units and is fully penetrant at 40 units and above (2, 3). There is an inverse correlation between expanded CAG repeat size and age at onset of symptoms (4-6). Although the mutation is well defined, the pathogenic process is not sufficiently understood to enable effective treatment. The majority of HD research focuses on the brain where there is characteristic neuropathology, primarily atrophy of the striatum (7).Alongside the striking neurological phenotype of HD, there is a generalized metabolic disruption. HD mutation carriers weigh less on average than non-HD individuals (8). Weight loss begins presymptomatically (9, 10), and in symptomatic individuals, energy expenditure far exceeds that utilized in movement, despite high calor...

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

“…For example, it was reported that brains of patients suffering from Huntington's disease (HD) contain about threefold more urea compared to the healthy controls (Patassini et al 2015). These findings have been proved in a transgenic sheep model of HD (Handley et al 2017) Additionally, the data indicating that the postmortem brains of AD patients contain significantly higher concentrations of urea compared to the control group have been published recently (Xu et al 2016). Consequently, the hypothesis linking build-up of urea in the brain to toxic levels causing brain damage and finally dementia was proposed (Handley et al 2017).…”

Arginase as a Potential Target in the Treatment of Alzheimer’s Disease

“…This finding has been verified in a transgenic sheep model of HD [77]. Consequently, a hypothesis was proposed that links the build-up of urea in the brain to toxic levels, causing brain damage and, finally, dementia [77].…”

“…For example, it has been reported that the brains of patients suffering from Huntington's disease (HD) contain about threefold more urea compared to healthy controls [76]. This finding has been verified in a transgenic sheep model of HD [77]. Consequently, a hypothesis was proposed that links the build-up of urea in the brain to toxic levels, causing brain damage and, finally, dementia [77].…”

Altered Plasma Acylcarnitines and Amino Acids Profile in Spinocerebellar Ataxia Type 7

“…The enrichment analysis also revealed defective ammonia recycling in SCA7. Since ammonia easily crosses the blood-brain barrier, blood-derived ammonia leads to neurotoxic levels of ammonia in the brain [44]. Aside from primarily affecting the brain, the toxicity of ammonia has also been demonstrated to affect other organs and tissues, including muscle.…”

“…Therefore, muscle mass depletion further reduces the body's capacity to clear ammonia, which in turn leads to a higher risk of developing hyperammonemia. Interestingly, both HD and SCA7 patients have elevated plasma ammonia levels [44], therefore it is tempting to speculate that dysregulated brain energy metabolism in SCA7 patients could be facilitated, at least in part, through imbalances in ammonia homeostasis.…”