uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
CSF Proenkephalin decreases with the progression of Huntington's disease
(Landtblom)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.ORCID iD: 0000-0001-9567-470x
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.ORCID iD: 0000-0001-9776-7715
Sahlrenska akademin, Göteborgs universitet.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 presymptomatic gene expansion carriers (pGEC) and 38 controls. In ManHD compared to pGEC 10 proteins were downregulated, and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin along with upregulated proteins (VASN, STC2, SGCE and C7) were all closely linked to HD symptom severity. The decreased PENK levels were replicated in a separate cohort of 23 ManHD and 23 controls where absolute quantitation was performed. We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK, and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD.   

Keywords [en]
Proteomics, Mass spectrometry, Neurodegeneration, Cerebrospinal fluid, Huntington's disease
National Category
Neurology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-395606OAI: oai:DiVA.org:uu-395606DiVA, id: diva2:1365220
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23
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)
Opponent
Supervisors
Available from: 2019-11-19 Created: 2019-10-23 Last updated: 2020-01-10

Open Access in DiVA

No full text in DiVA

Authority records BETA

Niemelä, ValterLandtblom, Anne-MarieNyholm, DagShevchenko, GannaBergquist, JonasSundblom, Jimmy

Search in DiVA

By author/editor
Niemelä, ValterLandtblom, Anne-MarieNyholm, DagShevchenko, GannaBergquist, JonasSundblom, Jimmy
By organisation
Landtblom: NeurologyDepartment of NeuroscienceAnalytical ChemistryScience for Life Laboratory, SciLifeLabEnblad: Neurosurgery
Neurology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 113 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf