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Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases
Open AccessArticle

CSF Ubiquitin Levels Are Higher in Alzheimer’s Disease than in Frontotemporal Dementia and Reflect the Molecular Subtype in Prion Disease

1
Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40138 Bologna, Italy
2
Department of Neurology, Ulm University Hospital, 89081 Ulm, Germany
3
IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
4
Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2020, 10(4), 497; https://doi.org/10.3390/biom10040497
Received: 9 March 2020 / Revised: 23 March 2020 / Accepted: 23 March 2020 / Published: 25 March 2020
(This article belongs to the Special Issue Prion Disease Biomarkers: Recent Advances)
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. View Full-Text
Keywords: biomarkers; human prion disease; Creutzfeldt–Jakob disease; Alzheimer’s disease; frontotemporal dementia; neurofilament ligh chain; ubiquitin; mass spectrometry; chitinase-3-like protein 1 biomarkers; human prion disease; Creutzfeldt–Jakob disease; Alzheimer’s disease; frontotemporal dementia; neurofilament ligh chain; ubiquitin; mass spectrometry; chitinase-3-like protein 1
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Abu-Rumeileh, S.; Oeckl, P.; Baiardi, S.; Halbgebauer, S.; Steinacker, P.; Capellari, S.; Otto, M.; Parchi, P. CSF Ubiquitin Levels Are Higher in Alzheimer’s Disease than in Frontotemporal Dementia and Reflect the Molecular Subtype in Prion Disease. Biomolecules 2020, 10, 497.

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