Mass Spectrometric Analysis of Cerebrospinal Fluid Ubiquitin in Alzheimer's Disease and Parkinsonian Disorders

Portelius

Journal of Neurochemistry

et al. 2018

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Neurodegenerative dementias constitute a broad group of diseases in which abnormally folded proteins accumulate in specific brain regions and result in tissue reactions that eventually cause neuronal dysfunction and degeneration. Depending on where in the brain this happens, symptoms appear which may be used to classify the disorders on clinical grounds. However, brain changes in neurodegenerative dementias start to accumulate many years prior to symptom onset and there is a poor correlation between the clinical picture and what pathology that is the most likely to cause it. Thus, novel drug candidates having disease-modifying effects that is targeting the underlying pathology and changes the course of the disease needs to be defined using objective biomarker-based measures since the clinical symptoms are often non-specific and overlap between different disorders. Furthermore, the treatment should ideally be initiated as soon as symptoms are evident or when biomarkers confirm an underlying pathology (pre-clinical phase of the disease) to reduce irreversible damage to, for example, neurons, synapses and axons. Clinical trials in the pre-clinical phase bring a greater importance to biomarkers since by definition the clinical effects are difficult or slow to discern in a population that is not yet clinically affected. Here, we discuss neuropathological changes that may underlie neurodegenerative dementias, including how they can be detected and quantified using currently available biofluid-based biomarkers and how more of them could be identified using targeted proteomics approaches.

“…; Sjödin et al . ) it exhibited increased CSF concentrations compared to controls. In a study comparing MCI‐AD to MCI‐stable and controls (Simonsen et al .…”

Section: Biomarkers For Dysfunctional Proteostasismentioning

confidence: 82%

“…; Sjödin et al . ). Similarly, ubiquitin levels in PSP have been reported to be similar as to controls (Oeckl et al .…”

Section: Biomarkers For Dysfunctional Proteostasismentioning

confidence: 97%

Fluid‐based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases

Portelius

Journal of Neurochemistry

et al. 2018

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Section: Introductionmentioning

confidence: 99%

“…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]. In physiological conditions, there is a tight regulation of the level of intracellular ubiquitin through the balance between free mono-and conjugated ubiquitin and the respective polyubiquitin chains [5,7]. However, a wealth of evidence suggests that a dysfunctional proteostasis in NDs related to both aging and the inhibitory effect of misfolded protein aggregates may cause an accumulation of ubiquitin in the brain [5,8,9].…”

Section: Introductionmentioning

confidence: 99%

“…In physiological conditions, there is a tight regulation of the level of intracellular ubiquitin through the balance between free mono-and conjugated ubiquitin and the respective polyubiquitin chains [5,7]. However, a wealth of evidence suggests that a dysfunctional proteostasis in NDs related to both aging and the inhibitory effect of misfolded protein aggregates may cause an accumulation of ubiquitin in the brain [5,8,9]. Moreover, ubiquitin can be released by dying cells, thereby increasing its level in the cerebrospinal fluid (CSF) as a consequence of neuronal damage [4,5,10].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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.

Alz & Dem Diag Ass & Dis Mo

Endo‐lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation

Toft

Sjödin

Simonsen

et al. 2023

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Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family.Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein.Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD.