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Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.ORCID iD: 0000-0002-4137-5517
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4129Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 4129
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-379886DOI: 10.1038/s41598-019-40186-5ISI: 000460754600020PubMedID: 30858393OAI: oai:DiVA.org:uu-379886DiVA, id: diva2:1298634
Funder
Åke Wiberg FoundationEU, Horizon 2020, 654241Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-10-23Bibliographically approved
In thesis
1. Mapping the Huntington's disease process using cerebrospinal fluid analysis
Open this publication in new window or tab >>Mapping the Huntington's disease process using cerebrospinal fluid analysis
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a CAG-repeat expansion in the HTT-gene. Today there are no disease-modifying therapies (DMTs), but several promising clinical trials are underway, including therapies that reduce mutant huntingtin expression.

Reliable biomarkers could empower such trials and guide the timing for initiation of future DMTs.

Neurofilament light (NFL) and tau, which are cerebrospinal fluid markers of neuronal death, have been implicated as markers of disease progression. Increased levels of the inflammatory marker YKL-40 have also been reported in HD.

The aim was to validate and compare the above biomarker candidates by targeted analyses, while explorative liquid chromatography-mass spectrometry (LC-MS) was used to identify new candidates. Clinically well-characterized HD patients, premanifest gene expansion carriers (pGECs), and controls were enrolled from Uppsala University Hospital in Sweden.

In contrast to tau, NFL levels differed between all three groups and NFL had stronger correlations with symptom severity compared with total-tau and phospho-tau. Longitudinally, only NFL maintained intergroup differences and rose with disease progression.

Soluble CD27, a marker of T cell-mediated inflammation, differed between all three groups, with the highest levels in manifest HD, and mostly undetectable levels in controls. YKL-40 showed a non-significant trend toward increase in manifest HD. 

We applied LC-MS metabolomics and discovered a metabolite signature unique to manifest HD, with deranged tyrosine metabolism including L-DOPA, dopamine, and thyroxine. Utilizing LC-MS we also identified altered proteins in manifest HD, including proenkephalin that was decreased and associated with symptom severity. 

In conclusion, NFL may be used as a pharmacodynamic marker in intervention trials. Interestingly, elevated sCD27 implies a role of adaptive immunity before disease onset, but validation is needed. YKL-40 is not suitable as an early marker in HD. The CSF metabolome constitutes a new compartment of potential biomarkers but challenges in metabolite identification should be addressed in future studies. Proenkephalin levels potentially reflect the remaining number of striatal medium spiny neurons and hold promise as a marker of disease progression. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 56
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1608
Keywords
Neurodegeneration, Huntingtons disease, Neurogenetics, Neuroinflammation, Neurofilament light, tau, Proenkephalin
National Category
Medical and Health Sciences
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-393256 (URN)978-91-513-0795-4 (ISBN)
Public defence
2019-12-12, Gunnesalen, ing.10 Akademiska sjukhuset, Uppsala, 13:15 (English)
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Available from: 2019-11-19 Created: 2019-10-23 Last updated: 2019-11-19

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Herman, StephanieNiemelä, ValterEmami Khoonsari, PayamSundblom, JimmyBurman, JoachimLandtblom, Anne-MarieSpjuth, OlaNyholm, DagKultima, Kim

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