Clinical and Experimental Applications of Sodium Phenylbutyrate

Iannitti, Tommaso; Palmieri, Beniamino

doi:10.1007/bf03259725

Cited by 13 publications

(19 citation statements)

References 154 publications

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“…This RHCG-SLC14A1 correlation was not present in the control animals. As neurological disorders involving ammonia accumulation (for example, UCDs) can be well managed by a low-protein diet and therapies such as sodium phenylbutyrate (43,44), it is imperative that we determine whether levels of ammonia are altered in HD individuals, in addition to those of urea.…”

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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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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“…However, both PB and clofibric acid are significantly less potent BDK inhibitors (IC 50 of 53.1 and 812 μM, respectively), than (S)-CPP (IC 50 of 6.3 μM; Table 1). PB has multiple targets in cells (28) and is rapidly metabolized to PA in vivo (29); the latter metabolite is inefficient in abating BDK activity (IC 50 = 1.27 mM). Smaller BDK inhibitors such as (R)-and (S)-CIC are also competitive inhibitors of BCKDC (18) and have not been studied in vivo.…”

Section: Discussionmentioning

confidence: 99%

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

Tso¹,

Qi²,

Gui³

et al. 2013

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

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The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-α-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.branched-chain α-ketoacid dehydrogenase kinase inhibitor | structure-based inhibitor design | allosteric mechanisms | kinase-inhibitor complex structures | in vivo kinase inhibitor studies T he branched-chain amino acids (BCAA) leucine, isoleucine, and valine comprise 40% of essential amino acids in daily dietary intake (1). The catabolic pathways of BCAA begin with transamination by branched-chain aminotransferases giving rise to corresponding branch-chain α-ketoacids (BCKA). The second common step, the irreversible oxidative decarboxylation of BCKA, is catalyzed by the single mitochondrial branch-chain α-ketoacid dehydrogenase complex (BCKDC). The homeostasis of BCAA and BCKA in vivo is critical for health. The accumulation of BCAA and BCKA secondary to inherited BCKDC deficiency produces maple syrup urine disease (MSUD), which can lead to fatal acidosis, neurological derangement, and mental retardation (2, 3). In large-scale high-throughput metabolic profiling studies, high blood BCAA concentrations were found to be highly associated with the development of insulin resistance (4, 5) and can serve as useful metabolic markers in type 2 diabetes risk assessment (6, 7). Pathologic stresses produced by the accumulated BCKA are linked to congenital heart diseases and heart failure (8). The above findings underscore the pivotal role of aberrant BCAA metabolism in the pathogenesis of metabolic, cardiac, and neurological diseases.The 4.5-MDa human BCKDC consists of three catalytic components: a heterotetrameric (α 2 β 2 ) branched-chain α-ketoacid decarboxylase (E1), a homo-24 meric dihydrolipoyltransacylase (E2), and a homodimeric dihydrolipoamide dehydrogenase (E3). In addition, human BCKDC contains two regulatory enzymes: BCKD kinase (BDK) and BCKD phosphatase (BDP), the latter also called PP2Cm phosphatase; these enzymes tightly regulate activity of BCKDC through the phosphorylation (inactivation)/ dephosphorylation (activation) of the E1α subunits (9, 10). BCKDC is or...

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“…4-PBA is an orally bioavailable aromatic short-chain fatty acid and is used as United States Food and Drug Administration-approved drug (Buphenyl, Ucyclyd Pharma Inc.; Ammonaps, Orphan Europe of Immeuble "Le Guillaumet") for clinical use as an ammonia scavenger in long term treatment of hyperammonemia in urea cycle disorders (25,26). 4-PBA reduces ammonia levels in blood as it offers itself as an alternative to urea synthesis to excrete waste nitrogen from the body.…”

Section: Discussionmentioning

confidence: 99%

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

Kemter

Sklenak

Rathkolb

et al. 2014

Journal of Biological Chemistry

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Clinical and Experimental Applications of Sodium Phenylbutyrate

Cited by 13 publications

References 154 publications

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

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

Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

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