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

• Published in: Scientific reports Vol. 9; no. 1; p. 4129
• Main Authors: Herman, Stephanie, Niemelä, Valter, Emami Khoonsari, Payam, Sundblom, Jimmy, Burman, Joachim, Landtblom, Anne-Marie, Spjuth, Ola, Nyholm, Dag, Kultima, Kim
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.03.2019; Nature Publishing Group UK
• Subjects: Adult; Aged; Biomarkers - cerebrospinal fluid; Cerebrospinal fluid; Cognitive ability; Dihydroxyphenylalanine; Dopamine; Dopamine - cerebrospinal fluid; Female; Humans; Huntingtin; Huntington Disease - cerebrospinal fluid; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Levodopa; Levodopa - cerebrospinal fluid; Liquid chromatography; Male; Mass spectroscopy; Metabolites; Middle Aged; Neurological diseases; Phenotypes; Phenylalanine; Phenylalanine - cerebrospinal fluid; Polyglutamine; Risk assessment; Thyroxine; Thyroxine - cerebrospinal fluid; Trinucleotide repeats; Tyrosine; Tyrosine - cerebrospinal fluid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-40186-5

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.