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.
Highlights
Prion disease, Alzheimer’s disease (AD) and frontotemporal dementia (FTD) spectrum belong to the neurodegenerative dementias (NDs), which are protein misfolding disorders characterized by tissue deposition and intracerebral spread of amyloidogenic protein aggregates [1].Ubiquitin protein plays a central role in the degradation of proteins in the so-called ubiquitin-proteasome system and is a ubiquitous component of protein amyloid aggregates [2,3,4,5,6]
Both prion disease and AD cases showed higher levels of cerebrospinal fluid (CSF) ubiquitin compared to controls (p < 0.001 and p = 0.003, respectively), whereas in the FTD group ubiquitin values were within the normal range (Table 1, Figure 1A)
Ubiquitin levels were higher in prion disease than in AD and FTD cases (p < 0.001 for each comparison), with the latter group showing lower values compared to the former (p = 0.002) (Table 1, Figure 1A)
Summary
Alzheimer’s disease (AD) and frontotemporal dementia (FTD) spectrum belong to the neurodegenerative dementias (NDs), which are protein misfolding disorders characterized by tissue deposition and intracerebral spread of amyloidogenic protein aggregates [1].Ubiquitin protein plays a central role in the degradation of proteins in the so-called ubiquitin-proteasome system and is a ubiquitous component of protein amyloid aggregates [2,3,4,5,6]. We have developed a very selective and precise liquid chromatography−multiple reaction monitoring mass spectrometry (LC−MS/MS) method for the measurement of CSF free monoubiquitin and already reported a significant increase in protein levels in Creutzfeldt–Jakob disease (CJD) and AD, in line with other studies investigating the same or other ubiquitin forms [3,4,5,6,9,11]. No study to date investigated whether the significant clinicopathological heterogeneity of the prion disease spectrum may influence CSF ubiquitin levels. Sporadic CJD (sCJD) includes six major clinicopathological subtypes that are mainly determined by the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the PRNP gene and the type (1 or 2) of disease-associated prion protein (PrPSc) accumulating in the brain, and named as MM(V), MM2 cortical (MM2C), MM2 thalamic (MM2T), MV2 kuru-type (MV2K), VV1, and VV2 [12]
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