Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington’s disease subjects.

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington’s disease subjects.

Publication date: Mar 11, 2019

Huntington’s disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

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Herman, S., , Niemel”a, Emami Khoonsari, P., Sundblom, J., Burman, J., Landtblom, A.M., Spjuth, O., Nyholm, D., and Kultima, K. Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington’s disease subjects. 06396. 2019 Sci Rep (9):1.

Concepts Keywords
Biochemical Phenylalanine
Cerebrospinal Fluid Huntingtin
Cognitive Tyrosine
DOPA Metabolome
Dopamine Catecholamines
Gene Proteinogenic amino acids
Huntingtin Ketogenic amino acids
Huntington Glucogenic amino acids
Mass Spectrometry Aromatic amino acids
Metabolome Amino acids
Neurological Chemical compounds
Pathogenesis Branches of biology
Phenotype
Phenylalanine
Purine
Sci
Thyroxine
Tyrosine
Tyrosine Metabolism

Semantics

Type Source Name
disease MESH estrogen
pathway BSID Aging
disease MESH aging
drug DRUGBANK Isoxaflutole
drug DRUGBANK Serotonin
drug DRUGBANK Norepinephrine
drug DRUGBANK Riboflavin
pathway BSID Riboflavin metabolism
drug DRUGBANK Methionine
drug DRUGBANK L-Threonine
drug DRUGBANK Serine
drug DRUGBANK Coenzyme A
drug DRUGBANK Inosine
drug DRUGBANK Cyclic Adenosine Monophosphate
drug DRUGBANK Hypoxanthine
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
pathway BSID Neurodegenerative Diseases
gene UNIPROT SOD1
gene UNIPROT IGFALS
drug DRUGBANK Amino acids
disease DOID amyotrophic lateral sclerosis
disease MESH amyotrophic lateral sclerosis
drug DRUGBANK Liothyronine
disease MESH neurodegenerative disorders
gene UNIPROT EGLN2
gene UNIPROT PLEC
gene UNIPROT HDAC1
drug DRUGBANK N-Acetylalanine
gene UNIPROT EGLN1
gene UNIPROT HDAC2
gene UNIPROT PDC
pathway BSID Tryptophan metabolism
disease DOID ers
gene UNIPROT MARK1
gene UNIPROT DYRK3
gene UNIPROT IK
gene UNIPROT HDC
gene UNIPROT HECA
drug DRUGBANK Adenine
gene UNIPROT APEH
drug DRUGBANK L-Tryptophan
disease MESH tryptophan
gene UNIPROT OCA2
gene UNIPROT B3GALNT1
drug DRUGBANK Proline
disease MESH **p
gene UNIPROT KNL1
pathway BSID Nitrogen metabolism
pathway BSID Isoleucine Biosynthesis
pathway BSID Tryptophan Biosynthesis
pathway BSID tryptophan biosynthesis
drug DRUGBANK Acetylcarnitine
drug DRUGBANK S-adenosyl-L-homocysteine
drug DRUGBANK Adenosine
drug DRUGBANK Creatinine
pathway BSID Purine metabolism
pathway BSID isoleucine degradation
pathway BSID Isoleucine Degradation
drug DRUGBANK L-Leucine
drug DRUGBANK L-Valine
pathway BSID Phenylalanine metabolism
drug DRUGBANK L-Isoleucine
drug DRUGBANK Xanthine
gene UNIPROT REST
gene UNIPROT PCSK4
gene UNIPROT IFRD1
gene UNIPROT SUB1
gene UNIPROT KRT17
gene UNIPROT PCSK2
gene UNIPROT KRT6B
gene UNIPROT CBX4
gene UNIPROT PKD2
gene UNIPROT KRT16
gene UNIPROT PCSK1
gene UNIPROT PKD1
disease MESH separated
gene UNIPROT DEPP1
gene UNIPROT GOPC
gene UNIPROT TNFRSF11A
gene UNIPROT IMPACT
disease MESH multiple
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Saquinavir
gene UNIPROT VIP
gene UNIPROT SET
gene UNIPROT CTSC
gene UNIPROT FLVCR1
drug DRUGBANK Pidolic Acid
disease DOID PCA
drug DRUGBANK Esomeprazole
gene UNIPROT ARNTL
gene UNIPROT PSD4
disease MESH TIC
drug DRUGBANK Ademetionine
drug DRUGBANK Water
drug DRUGBANK Formic Acid
gene UNIPROT RORC
gene UNIPROT CES2
gene UNIPROT CASP1
gene UNIPROT LRP2
gene UNIPROT MCF2L
gene UNIPROT PYCARD
gene UNIPROT TYMS
drug DRUGBANK Tilmicosin
gene UNIPROT RASA1
gene UNIPROT RGS6
gene UNIPROT MENT
drug DRUGBANK Trestolone
pathway BSID Phospholipid metabolism
gene UNIPROT SLC35G1
pathway BSID Metabolism
pathway BSID Oxidative Damage
gene UNIPROT LARGE1
gene UNIPROT DAG1
drug DRUGBANK Stearic acid
drug DRUGBANK Coenzyme M
disease MESH development
gene UNIPROT SLC6A4
drug DRUGBANK 7 8-dimethylalloxazine
drug DRUGBANK Dopamine
drug DRUGBANK Levodopa
pathway BSID Tyrosine metabolism
gene UNIPROT LAMC2
gene UNIPROT CSF2
gene UNIPROT FBN1
gene UNIPROT HTT
disease MESH cognitive decline
drug DRUGBANK L-Phenylalanine
drug DRUGBANK L-Tyrosine

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