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CSF Proenkephalin decreases with the progression of Huntington's disease
(Landtblom)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Landtblom: Neurologi.ORCID-id: 0000-0001-9567-470x
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.ORCID-id: 0000-0001-9776-7715
Sahlrenska akademin, Göteborgs universitet.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
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.   

Nyckelord [en]
Proteomics, Mass spectrometry, Neurodegeneration, Cerebrospinal fluid, Huntington's disease
Nationell ämneskategori
Neurologi
Forskningsämne
Neurologi
Identifikatorer
URN: urn:nbn:se:uu:diva-395606OAI: oai:DiVA.org:uu-395606DiVA, id: diva2:1365220
Tillgänglig från: 2019-10-23 Skapad: 2019-10-23 Senast uppdaterad: 2019-10-23
Ingår i avhandling
1. Mapping the Huntington's disease process using cerebrospinal fluid analysis
Öppna denna publikation i ny flik eller fönster >>Mapping the Huntington's disease process using cerebrospinal fluid analysis
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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. 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 56
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1608
Nyckelord
Neurodegeneration, Huntingtons disease, Neurogenetics, Neuroinflammation, Neurofilament light, tau, Proenkephalin
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-393256 (URN)978-91-513-0795-4 (ISBN)
Disputation
2019-12-12, Gunnesalen, ing.10 Akademiska sjukhuset, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-11-19 Skapad: 2019-10-23 Senast uppdaterad: 2020-01-10

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

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Niemelä, ValterLandtblom, Anne-MarieNyholm, DagShevchenko, GannaBergquist, JonasSundblom, Jimmy
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Landtblom: NeurologiInstitutionen för neurovetenskapAnalytisk kemiScience for Life Laboratory, SciLifeLabEnblad: Neurokirurgi
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