High Protein Diet and Huntington's Disease

Chen, Chiung‐Mei; Lin, Yow-Sien; Wu, Yih‐Ru; Chen, Pei; Tsai, Fuu‐Jen; Yang, Chueh-Lien; Tsao, Ya-Tzu; Chang, Wen Yin; Hsieh, I-Shan; Chern, Yijuang; Soong, Bing‐Wen

doi:10.1371/journal.pone.0127654

Cited by 14 publications

(20 citation statements)

References 33 publications

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“…Our findings corroborate previous studies reporting raised blood citrulline levels in patients with HD and in two mice models (R6/2 and HdhQ150; ref. 43 ) and are consistent with abnormalities in the urea and NO cycles. A suggested mechanism is that disruption of CCAAT-enhancer-binding proteins (C/EBP) activity by mutant huntingtin 44 causes suppression of the expression of two key enzymes (argininosuccinic acid synthetase and argininosuccinase acid lyase) of the urea cycle 44 .…”

Section: Discussionsupporting

confidence: 67%

“…Dietary supplementation of arginine in HD mice hastens disease progression (demonstrated by increased weight loss and abnormal motor function; ref. 43 ). Furthermore, in a number of other studies NO and NOS have been linked either directly or indirectly to many aspects of HD pathology, such as oxidative stress 45 , mitochondrial dysfunction 46 47 , platelet signalling 48 and peripheral vasodilatation 49 .…”

Section: Discussionmentioning

confidence: 99%

“…Together these data point to abnormalities in the urea cycle and NO cycle, as has been suggested in HD mice 44 49 50 . Interestingly, a low protein diet (17%) restores urea cycle activity and ameliorates symptoms in HD model mice 43 . In support of possible NO disturbances in HD, the HD sheep also had significantly raised levels of ADMA and SDMA compared to control sheep.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

Skene

Middleton

Fraser

et al. 2017

Sci Rep

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The pronounced cachexia (unexplained wasting) seen in Huntington’s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25 h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

Skene

Middleton

Fraser

et al. 2017

Sci Rep

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Handley

Reid

Bräuning

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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...

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“…Some studies investigated the nutritional status of people with HD to determine whether micronutrient and macronutrient intake helped in improving disease symptoms or delaying disease progression [ 18 , 30 , 31 , 32 ].…”

Section: Resultsmentioning

confidence: 99%

Dietary Intake, Mediterranean Diet Adherence and Caloric Intake in Huntington’s Disease: A Review

2020

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Decades of research and experimental studies have investigated Huntington’s disease (HD), a rare neurodegenerative disease. Similarly, several studies have investigated whether high/moderate adherence to the Mediterranean Diet and specific macro and micronutrients can decrease cognitive loss and provide a neuroprotective function to neurons. This review systematically identifies and examines studies that have investigated Mediterranean Diet adherence, micro- and macronutrients, supplementation and caloric intake in people with HD, in order to identify if dietary exposures resulted in improvement of disease symptoms, a delay in age of onset or if they contributed to an earlier age of onset in people with HD. A systematic search of PubMed, Directory of open access journal and HubMed was performed independently by two reviewers using specific search terms criteria for studies. The identified abstracts were screened and the studies were included in the review if they satisfied predetermined inclusion criteria. Reference screening of included studies was also performed. A total of 18 studies were included in the review. A few studies found that patients who had high/moderate adherence to Mediterranean Diet showed a slight improvement in their Unified Huntington’s Disease Rating Scale and Total Functional Capacity. In addition, people with HD who had high Mediterranean Diet adherence showed an improvement in both cognitive and motor scores and had a better quality of life compared to patients who had low Mediterranean Diet adherence. Furthermore, a few studies showed that supplementation with specific nutrients, such as triheaptanoin, L-acetyl-carnitine and creatine, had no beneficial effect on the patients’ Unified Huntington’s Disease Rating Scale score. A few studies suggest that the Mediterranean Diet may confer a motor and cognitive benefit to people with HD. Unfortunately, there was little consistency among study findings. It is important for more research to be conducted to have a better understanding of which dietary exposures are beneficial and may result delaying age of onset or disease progression in people with HD.

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High Protein Diet and Huntington's Disease

Cited by 14 publications

References 33 publications

Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

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

Dietary Intake, Mediterranean Diet Adherence and Caloric Intake in Huntington’s Disease: A Review

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