There is ample biochemical, pathological, and genetic evidence that the metabolism of α-synuclein (α-syn) plays a crucial role in the pathogenesis of Parkinson disease (PD). To examine whether ...quantification of α-syn in cerebrospinal fluid (CSF) is potentially informative in the diagnosis of PD, we developed a specific ELISA system and measured the concentration of α-syn in CSF from 33 patients with PD (diagnosed according to UK PD Society Brain Bank criteria) and 38 control subjects including 9 neurologically healthy individuals. We found that PD patients had significantly lower α-syn levels in their CSF than the control groups (
p
<
0.0001) even after adjusting for gender and age. Age was independently associated with lower α-syn levels. Logistic regression analysis showed that reduction in CSF α-syn served as a significant predictor of PD beyond age and gender alone (area under ROC curve,
c
=
0.882). Furthermore, we observed a close inverse correlation between α-syn levels in CSF and assigned Hoehn and Yahr score in this cohort of 71 living subjects (
p
<
0.0001), even after adjusting for age. These findings identify in the quantification of α-syn from CSF a potential laboratory marker to aid the clinical diagnosis of PD.
γ-Synuclein and the progression of cancer Ahmad, Mushfika; Attoub, Samir; Singh, Maneesh N ...
The FASEB journal,
November 2007, Letnik:
21, Številka:
13
Journal Article
Recenzirano
The synucleins are a small, soluble, highly conserved group of neuronal proteins that have been implicated in both neurodegenerative diseases and cancer. The synuclein family consists of α-, β-, and ...γ-synucleins (γ-syn). They are a natively unfolded group of proteins that share sequence homologies and structural properties (1, 2). So far, the biological functions of the synucleins are still unclear, but their involvement in neurodegenerative diseases and cancer may provide insights into the pathological processes that result from these two groups of debilitating diseases, and present the possibility to use them as potential targets for early diagnosis and treatment. Recently, elevated levels of γ-syn proteins have been detected in various types of cancer, especially in advanced stages of the disease. Furthermore, studies to date indicate that overexpression of γ-syn compromises normal mitotic checkpoint controls, resulting in multinucleation as well as faster cell growth. γ-Syn has also been shown to promote invasion and metastasis in in vitro assays as well as in animal models. Overexpression of γ-syn also interferes with drug-induced apoptotic responses. These observations raise questions about the involvement of γ-syn in the process of tumorigenesis and metastasis, and efforts have already been made to use γ-syn as a marker for assessing breast cancer progression (3). This review will discuss the involvement of γ-syn in cancer progression, metastasis and its potential as a marker.--Ahmad, M., Attoub, S., Singh, M. N., Martin, F. L., El-Agnaf, O. M. A. γ-Synuclein and the progression of cancer.
A novel Lamb wave resonator with fully suppressed acoustic radiation in water is proposed for high-resolution mass-sensitive detection of biomolecules. The elimination of acoustic radiation is ...achieved by slowing down the Lamb wave to a velocity lower than the sound speed in water. This enables high-quality-factor resonance in water and reduces the sensing frequency noise. High aspect ratio electrodes (HAREs) are used to slow down the Lamb wave. The elastic resonance and large surface area of the HAREs can also enhance the mass sensitivity of the device. The improved mass sensitivity together with the low frequency noise substantially improves the overall sensing resolution. Although reducing the plate thickness can also slow down the Lamb wave, it makes the device very fragile and not practical to use. In contrast, slowing down the Lamb wave by increasing electrode height allows the use of thick plates which is robust. In this article, the behavior and performance of the proposed high aspect ratio electrode Lamb wave resonator (HARE-LWR) are theoretically analyzed using finite element method simulations. Optimum design parameters were found through the simulations. Reported results show that a significant figure of merit improvement was achieved by the proposed HARE-LWR design.
The objective was to study whether α-synuclein oligomers are altered in the cerebrospinal fluid (CSF) of patients with dementia, including Parkinson disease with dementia (PDD), dementia with Lewy ...bodies (DLB), and Alzheimer disease (AD), compared with age-matched controls.
In total, 247 CSF samples were assessed in this study, including 71 patients with DLB, 30 patients with PDD, 48 patients with AD, and 98 healthy age-matched controls. Both total and oligomeric α-synuclein levels were evaluated by using well-established immunoassays.
The levels of α-synuclein oligomers in the CSF were increased in patients with PDD compared with the controls (P < 0.05), but not in patients with DLB compared with controls. Interestingly, the levels of α-synuclein oligomers in the CSF were also significantly higher in patients with PDD (P < 0.01) and DLB (P < 0.05) compared with patients with AD. The levels of CSF α-synuclein oligomers and the ratio of oligomeric/total-α-synuclein could distinguish DLB or PDD patients from AD patients, with areas under the curves (AUCs) of 0.64 and 0.75, respectively. In addition, total-α-synuclein alone could distinguish DLB or PDD patients from AD patients, with an AUC of 0.80.
The levels of α-synuclein oligomers were increased in the CSF from α-synucleinopathy patients with dementia compared with AD cases.
Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar ...deposits of the β-amyloid peptide (Aβ) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early “soluble oligomers” are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of Aβ, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of Aβ and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Aβ-(1–40) and ABri and found that in both cases it was generated as a short “burst” early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling “soluble oligomers” or “protofibrils” were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Aβ-(1–40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.
Abstract Phosphorylation of the α-synuclein (α-syn) protein at Ser129 P(S129)-α-syn was found to be the most abundant form in intracellular inclusions in brains from Parkinson's disease (PD) ...patients. This finding suggests that P(S129)-α-syn plays a central role in the pathogenesis of PD. However, it is at present unclear whether P(S129)-α-syn is pathogenic driving the neurodegenerative process. Rodent studies using neither the phosphomimics of human α-syn nor co-expression of human wild-type α-syn and kinases phosphorylating α-syn at Ser129 gave consistent results. One major concern in interpreting these findings is that human α-syn was expressed above physiological levels inducing neurodegeneration in rat nigral neurons. In order to exclude this confounding factor, we took a different approach and increased the phosphorylation level of endogenous α-syn. For this purpose, we took advantage of recombinant adeno-associated viral (rAAV) vectors to deliver polo-like kinase (PLK) 2 or PLK3 in the substantia nigra and investigated whether increased levels of P(S129)-α-syn compromised the function and survival of nigral dopaminergic neurons. Interestingly, we observed that hyperphosphorylated α-syn did not induce nigral dopaminergic cell death, as assessed at 1 and 4 months. Furthermore, histological analysis did not show any accumulation of α-syn protein or formation of inclusions. Using in vivo microdialysis, we found that the only measurable functional alteration was the depolarisation-induced release of dopamine, while the in vivo synthesis rate of DOPA and dopamine baseline release remained unaltered. Taken together, our results suggest that phosphorylation of α-syn at Ser129 does not confer a toxic gain of function per se.
Cognitive dysfunctions such as mild cognitive impairment (MCI), Alzheimer's disease (AD), and other forms of dementia are recognized as common comorbidities of type 2 diabetes mellitus (T2DM). ...Currently, there are no disease-modifying therapies or definitive clinical diagnostic and prognostic tools for dementia, and the mechanisms underpinning the link between T2DM and cognitive dysfunction remain equivocal. Some of the suggested pathophysiological mechanisms underlying cognitive decline in diabetes patients include hyperglycemia, insulin resistance and altered insulin signaling, neuroinflammation, cerebral microvascular injury, and buildup of cerebral amyloid and tau proteins. Given the skyrocketing global rates of diabetes and neurodegenerative disorders, there is an urgent need to discover novel biomarkers relevant to the co-morbidity of both conditions to guide future diagnostic approaches. This review aims to provide a comprehensive background of the potential risk factors, the identified biomarkers of diabetes-related cognitive decrements, and the underlying processes of diabetes-associated cognitive dysfunction. Aging, poor glycemic control, hypoglycemia and hyperglycemic episodes, depression, and vascular complications are associated with increased risk of dementia. Conclusive research studies that have attempted to find specific biomarkers are limited. However, the most frequent considerations in such investigations are related to C reactive protein, tau protein, brain-derived neurotrophic factor, advanced glycation end products, glycosylated hemoglobin, and adipokines.
Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson's disease (PD). In this study, we aim to ...identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers.
We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aβ-40), amyloid-beta-42 (Aβ-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD.
Discriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve > 0.80 was generated.
The current study suggests that CSF t-, o-α-syn and TNF-α are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers' panel approach for an accurate and timely diagnosis of PD.
α‐Synuclein is the major component of Lewy bodies and a candidate biomarker for neurodegenerative diseases in which Lewy bodies are common, including Parkinson's disease and dementia with Lewy ...bodies. A large body of literature suggests that these disorders are characterized by reduced concentrations of α‐synuclein in cerebrospinal fluid (CSF), with overlapping concentrations compared to healthy controls and variability across studies. Several reasons can account for this variability, including technical ones, such as inter‐assay and inter‐laboratory variation (reproducibility). We compared four immunochemical methods for the quantification of α‐synuclein concentration in 50 unique CSF samples. All methods were designed to capture most of the existing α‐synuclein forms in CSF (‘total’ α‐synuclein). Each of the four methods showed high analytical precision, excellent correlation between laboratories (R2 0.83–0.99), and good correlation with each other (R2 0.64–0.93), although the slopes of the regression lines were different between the four immunoassays. The use of common reference CSF samples decreased the differences in α‐synuclein concentration between detection methods and technologies. Pilot data on an immunoprecipitation mass spectrometry (IP‐MS) method is also presented. Our results suggest that the four immunochemical methods and the IP‐MS method measure similar forms of α‐synuclein and that a common reference material would allow harmonization of results between immunoassays.
α‐Synuclein is a synaptic protein that forms intracellular Lewy body inclusions in Parkinson's disease and other so called synuclein aggregation disorders. There are several methods to measure α‐synuclein concentration in human cerebrospinal fluid, where it is a candidate diagnostic and prognostic biomarker. In the current paper, we compared the analytical characteristics of four immunochemical (MSD, BioLegnd, Adx, and Roche) and one mass spectrometry‐based method. Variance component analysis partitions the total variance associated with 49 sample measured by site, kit lot, and replicate. The results show that the different methods measure similar forms of α‐synuclein and that a common reference material would allow for assay harmonization, which will be important in studies evaluating drugs that target α‐synuclein pathology specifically.
Recent studies have shown that cerebrospinal fluid (CSF) levels of α-synuclein (α-syn) are highly elevated in patients with Creutzfeldt–Jakob disease (CJD) compared to controls. However, the ...diagnostic value of CSF α-syn in CJD has not been established. To confirm whether CSF α-syn is increased in CJD and is a useful marker for this disease, two independent enzyme-linked immunoabsorbent assays (ELISAs) specific for α-syn were used: ELISA 211-FL140, which is specific for full-length α-syn, and ELISA N19-FL140, which is specific for the full-length and associated C-terminal truncated forms of α-syn. CSF samples from 24 patients with CJD and 24 controls were assessed in this study. We found that samples from the CJD patients showed significantly higher levels of CSF α-syn compared to controls in both ELISA (211-FL140 or N19-FL140) tests (
P
= 0.0467 and
P
= 0.0010, respectively). However, there was a considerable overlap in the concentration ranges of the two groups of subjects. We also measured the levels of total tau (t-tau) protein in these samples and found that CSF t-tau levels were 5–10-times higher in the CJD group (
P
< 0.0001) compared with the controls. When the CSF t-tau and α-syn levels were combined, the area under the ROC curve (AUC) was slightly increased in clinically diagnosed CJD cases (AUC of 0.964) relative to an AUC of 0.943 for increased CSF t-tau alone. The combined use of CSF α-syn and t-tau levels may be a useful biomarker for the diagnosis of CJD.
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