Metabolic signatures of Huntington's disease (HD): 1 H NMR analysis of the polar metabolome in post-mortem human brain

Graham, Stewart F.; Kumar, Praveen; Bjorndahl, Trent C.; Han, Beom Soo; Yılmaz, Ali; Sherman, Eric; Wishart, David S.; Mann, David; Green, Brian D.

doi:10.1016/j.bbadis.2016.06.007

Cited by 46 publications

(47 citation statements)

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“…The decreased BCAA levels were also observed in the CSF of HD subjects [ 138 ]. In line with this evidence, another study identified reduced valine in both the striatum and frontal lobe of HD patients as compared to controls [ 142 ]. Remarkably, plasma BCAA levels were negatively correlated with the severity of motor dysfunction [ 139 ] and the number of CAG repeats in HD [ 139 , 140 ].…”

Section: Altered Bcaas Metabolism In Other Neurological Disordersmentioning

confidence: 57%

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Jakher

Ahrens‐Nicklas

2020

IJMS

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Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

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Section: Altered Bcaas Metabolism In Other Neurological Disordersmentioning

confidence: 57%

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Jakher

Ahrens‐Nicklas

2020

IJMS

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“…Topological pathway analysis was performed in MetaboAnalyst to identify the most perturbed biological pathways, as previously described . Briefly, the Rattus Norvegicus library was chosen, and the test for pathway enrichment analysis and relative‐betweenness centrality options for the pathway topology analyses were selected.…”

Section: Methodsmentioning

confidence: 99%

Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

Maerz

Sherman

Newton

et al. 2018

Journal Orthopaedic Research

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ACL rupture is a major risk factor for post-traumatic osteoarthritis (PTOA) development. Little information exists on acute systemic metabolic indicators of disease development. Thirty-six female Lewis rats were randomized to Control or noninvasive anterior cruciate ligament rupture (ACLR) and to three post-injury time points: 72 h, 4 weeks, 10 weeks (n = 6). Serum was collected and analyzed by H nuclear magnetic resonance (NMR) spectroscopy and combined direct injection and liquid chromatography (LC)-mass spectrometry (MS)/MS (DI-MS). Univariate and multivariate statistics were used to analyze metabolomic data, and predictive biomarker models were analyzed by receiver operating characteristic (ROC) analysis. Topological pathway analysis was used to identify perturbed pathways. Two hundred twenty-two metabolites were identified by H NMR and DI-MS. Differences in the serum metabolome between ACLR and Control were dominated by medium- and long-chain acylcarnitine species. Further, decreases in several tryptophan metabolites were either found to be significantly different in univariate analysis or to play important contributory roles to multivariate model separation. In addition to acylcarnitines and tryptophan metabolites, glycine, carnosine, and D-mannose were found to differentiate ACLR from Control. Glycine, 9-hexadecenoylcarnitine, trans-2-Dodecenoylcarnitine, linoelaidyl carnitine, hydroxypropionylcarnitine, and D-Mannose were identified as biomarkers with high area under ROC curve values and high predictive accuracies. Our analysis provides new information regarding the potential contribution of inflammatory processes and immune dysregulation to the onset and progression of PTOA following ACL injury. As these processes have most commonly been associated with inflammatory arthropathies, larger-scale studies elucidating their involvement in PTOA development and progression are necessary. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1969-1979, 2018.

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“…Consistent with this rise, the urea transporter UT-B present in astrocytes is elevated in postmortem human caudate and cortex, possibly to facilitate removal of the excess urea [ 194, 195 ]. A deficit in urea cycle functioning was noted in a prior report demonstrating decreases in post mortem striatal urea indicating additional work is needed to examine enzyme activities and to clarify how the urea cycle may be altered in HD [ 196 ].…”

Section: Energy Deficits In Hdmentioning

confidence: 99%

Towards an Understanding of Energy Impairment in Huntington’s Disease Brain

Dubinsky

2017

JHD

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This review systematically examines the evidence for shifts in flux through energy generating biochemical pathways in Huntington’s disease (HD) brains from humans and model systems. Compromise of the electron transport chain (ETC) appears not to be the primary or earliest metabolic change in HD pathogenesis. Rather, compromise of glucose uptake facilitates glucose flux through glycolysis and may possibly decrease flux through the pentose phosphate pathway (PPP), limiting subsequent NADPH and GSH production needed for antioxidant protection. As a result, oxidative damage to key glycolytic and tricarboxylic acid (TCA) cycle enzymes further restricts energy production so that while basal needs may be met through oxidative phosphorylation, those of excessive stimulation cannot. Energy production may also be compromised by deficits in mitochondrial biogenesis, dynamics or trafficking. Restrictions on energy production may be compensated for by glutamate oxidation and/or stimulation of fatty acid oxidation. Transcriptional dysregulation generated by mutant huntingtin also contributes to energetic disruption at specific enzymatic steps. Many of the alterations in metabolic substrates and enzymes may derive from normal regulatory feedback mechanisms and appear oscillatory. Fine temporal sequencing of the shifts in metabolic flux and transcriptional and expression changes associated with mutant huntingtin expression remain largely unexplored and may be model dependent. Differences in disease progression among HD model systems at the time of experimentation and their varying states of metabolic compensation may explain conflicting reports in the literature. Progressive shifts in metabolic flux represent homeostatic compensatory mechanisms that maintain the model organism through presymptomatic and symptomatic stages.

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Metabolic signatures of Huntington's disease (HD): 1 H NMR analysis of the polar metabolome in post-mortem human brain

Cited by 46 publications

References 50 publications

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

Metabolomic serum profiling after ACL injury in rats: A pilot study implicating inflammation and immune dysregulation in post‐traumatic osteoarthritis

Towards an Understanding of Energy Impairment in Huntington’s Disease Brain

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