Biochemical and Biophysical Research Communications
Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease
Introduction
Huntington's disease is an autosomal dominant genetic disorder caused by an expanded CAG repeat in exon 1 of the HTT gene, which is located on chromosome 4 and encodes the huntingtin protein [1]. Biochemical pathways in which alterations have been linked to neurodegeneration in HD include cell-stress responses, apoptosis, several metabolic pathways including the ubiquitin-proteasome system and protein trafficking/endocytosis [2].
In manifest HD, progressive degeneration of the brain leads ultimately to symptoms including involuntary body movements (chorea), disturbances of speech, and progressive dementia [3]. Although the caudate-putamen and cerebral cortex are known primary targets of neurodegeneration in HD, it has been reported that several other brain regions are also affected in this complex disease process [4].
Besides the well-characterised neuropathology, several lines of evidence point to a widespread metabolic perturbation in HD. There is evidence that this mechanism is not limited to the basal ganglia and associated neural circuitry; rather, it is thought to be pervasive, affecting many brain regions in HD-gene carriers [5], [6]. Furthermore, the existence of a systemic metabolic defect is also supported in HD [7], [8], [9].
In order to study the effects of HD on metabolism across the affected brain, we chose to apply gas chromatography/mass spectrometry-based metabolomics to detect and characterise putative alterations in metabolite levels in short post-mortem-delay brain tissue of patients and matched controls, using a case-control approach.
Eleven regions of the human brain were analysed here. The putamen and motor cortex were selected as they are most severely affected in advanced disease whereas sensory cortex, globus pallidus, cingulate gyrus and substantia nigra represent regions moderately affected in the HD brain [10], [11]. Finally, hippocampus, entorhinal cortex, cerebellum, middle frontal gyrus and middle temporal gyrus were included as they are not usually associated with overt degeneration.
Section snippets
Acquisition of human brains
Whole brains from nine HD patients and nine matched controls were obtained from the New Zealand Neurological Foundation Human Brain Bank, in the Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. All procedures in this study were approved by the University of Auckland Human Participants Ethics Committee with informed consent from all families. The quality of HD brain tissue acquired by the Auckland brain bank is uniformly high as
Results and discussion
We measured urea as mmol/kg of wet brain-tissue weight, in 11 brain regions from 9 patients with HD and 9 matched controls. Cases and controls were matched for male:female ratio, age, and post-mortem delay (Table 1). Brain-weights were significantly lighter in cases than in controls (P = 0.01). HD cases were all heterozygous for HTT mutations, and elevated CAG repeat-lengths ranged between 40 and 47 (Table 2).
Reproducibility of the GC-MS-derived measurements was verified by monitoring urea
Conflict of interest
None.
Acknowledgements
We thank all the families of patients with Huntington's disease in New Zealand who so generously supported this research through the donation of brain tissue to the NZ Neurological Foundation Human Brain Bank in the Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. This work was supported by the CHDI Foundation (A-8247); the Endocore Research Trust (61047); the Maurice and Phyllis Paykel Trust (3627036); the Neurological Foundation of New
References (28)
Huntington's disease: new paths to pathogenesis
Cell
(2004)- et al.
Genetics and neuropathology of Huntington's disease
Int. Rev. Neurobiol.
(2011) Alkylsilyl derivatives for gas chromatography
J. Chromatogr. A
(2013)- et al.
Studies on the free amino acids and related compounds in the tissues of the cat
J. Biol. Chem.
(1954) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
Cell
(1993)- et al.
Huntington's disease. Pathogenesis and management
N. Engl. J. Med.
(1986) - et al.
The neuropathology of Huntington's disease
Curr. Top. Behav. Neurosci.
(2015) - et al.
Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington's disease
Brain
(1996) - et al.
Metabolic network as a progression biomarker of premanifest Huntington's disease
J. Clin. Invest.
(2013) - et al.
Metabolic and hormonal signatures in pre-manifest and manifest Huntington's disease patients
Front. Physiol.
(2014)
Tryptophan metabolism and oxidative stress in patients with Huntington's disease
J. Neurochem.
Weight loss in early stage of Huntington's disease
Neurology
Neuropathological classification of Huntington's disease
J. Neuropathol. Exp. Neurol.
Development and performance of a gas chromatography-time-of-flight mass spectrometry analysis for large-scale nontargeted metabolomic studies of human serum
Anal. Chem.
Cited by (54)
High urea induces anxiety disorders associated with chronic kidney disease by promoting abnormal proliferation of OPC in amygdala
2023, European Journal of PharmacologyElevated hippocampal copper in cases of type 2 diabetes
2022, eBioMedicineManganese and related neurotoxic pathways: A potential therapeutic target in neurodegenerative diseases
2022, Neurotoxicology and TeratologyMetabolic changes in the brain and blood of rats following acoustic trauma, tinnitus and hyperacusis
2021, Progress in Brain ResearchCerebral deficiency of vitamin B5 (D-pantothenic acid; pantothenate) as a potentially-reversible cause of neurodegeneration and dementia in sporadic Alzheimer's disease
2020, Biochemical and Biophysical Research Communications
- 1
Equal contributions.