Csf ubiquitin levels are higher in alzheimer’s disease than in frontotemporal dementia and reflect the molecular subtype in prion disease

Samir Abu-Rumeileh, Patrick Oeckl, Simone Baiardi, Steffen Halbgebauer, Petra Steinacker, Sabina Capellari, Markus Otto, Piero Parchi

Research output: Contribution to journalArticlepeer-review

Abstract

Disturbances in the ubiquitin-proteasome system seem to play a role in neurodegenerative dementias (NDs). Previous studies documented an increase of cerebrospinal fluid (CSF) free monoubiquitin in Alzheimer’s disease (AD) and Creutzfeldt–Jakob disease (CJD). However, to date, no study explored this biomarker across the heterogeneous spectrum of prion disease. Using a liquid chromatography−multiple reaction monitoring mass spectrometry, we investigated CSF free monoubiquitin in controls (n = 28) and in cases with prion disease (n = 84), AD (n = 38), and frontotemporal dementia (FTD) (n = 30). Furthermore, in CJD subtypes, we evaluated by immunohistochemistry (IHC) the relative extent of brain ubiquitin deposits. Prion disease and, to a lesser extent, AD subjects showed increased levels of CSF free monoubiquitin, whereas FTD cases had median protein values similar to controls. The biomarker showed a good to optimal accuracy in the differential diagnosis between NDs and, most interestingly, between AD and FTD. After stratification, according to molecular subtypes, sporadic CJD VV2 demonstrated significantly higher levels of CSF ubiquitin and more numerous brain ubiquitin deposits at IHC in comparison to the typical and most prevalent MM(V)1 subtype. Moreover, CSF ubiquitin correlated with biomarkers of neurodegeneration and astrogliosis in NDs, and was associated with disease stage but not with survival in prion disease. The differential increase of CSF free monoubiquitin in prion disease subtypes and AD may reflect common, though disease and time-specific, phenomena related to neurodegeneration, such as neuritic damage, dysfunctional proteostasis, and neuroinflammation.

Original languageEnglish
Article number497
JournalBiomolecules
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 2020

Keywords

  • Alzheimer’s disease
  • Biomarkers
  • Chitinase-3-like protein 1
  • Creutzfeldt
  • Frontotemporal dementia
  • Human prion disease
  • Jakob disease
  • Mass spectrometry
  • Neurofilament ligh chain
  • Ubiquitin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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