Phosphorylated α-synuclein and phosphorylated tau-protein in sural nerves may contribute to differentiate Parkinson’s disease from multiple system atrophy and progressive supranuclear paralysis

Rong, Zhe; Shen, Feifei; Wang, Ye; Sun, Li; Wu, Jing; Zhang, Hui; Yuan, Yongsheng; Jiang, Wenwen; Xiao, Li; Pan, Jianji; Zhang, Kezhong

doi:10.1016/j.neulet.2021.135964

Cited by 9 publications

(6 citation statements)

References 30 publications

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“…The ThT endpoint fluorescence intensity of sTau-SAA was dramatically higher in AD than in synucleinopathies, whereas the skin-tau fluorescence intensity was significantly higher in synucleinopathies except for MSA than in the control group (Fig. 5), consistent with the previous observations that some of cases with synucleinopathies can have tau-pathology [10,19,37,44,48].…”

Section: The Stau-sa Of Ad and All Tauopathies Can Be Specifically Di...supporting

confidence: 91%

“…Accumulation of tau aggregates in the brain has been observed in synucleinopathies including PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [10, 19, 37, 44, 48]. Next, we further explored whether tau-SA can be detected in the skin of synucleinopathies by our sTau-SAA.…”

Section: Resultsmentioning

confidence: 99%

“…The sTau-SA is significantly higher in PD and dementia with Lewy bodies than in multiple system atrophy and normal controls but it is still lower than that in AD Accumulation of tau aggregates in the brain has been observed in synucleinopathies including PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [10,19,37,44,48].…”

Section: The Stau-sa Of Ad and All Tauopathies Can Be Specifically Di...mentioning

confidence: 99%

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Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

Wang,

Wu,

Gerasimenko

et al. 2023

Preprint

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Tauopathies are a group of age-related neurodegenerative diseases with a molecular hallmark of the prion-like propagation and accumulation of pathologically phosphorylated tau protein in the brain. They include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Currently, in the peripheral tissues and body fluids there are no reliable diagnostic biomarkers available that are able to directly reflect the capability of propagation and spreading of the misfolded tau aggregates. Here, we revealed significantly increased amounts of phosphorylated tau in the skin of AD patients compared to those in other tauopathies and normal controls. Moreover, the seed-amplification assay (SAA) by the ultrasensitive real-time quaking-induced conversion (RT-QuIC) displayed that the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies including AD, PSP, CBD, PiD was dramatically higher than that in normal controls, yielding 75-80% sensitivity and 95-100% specificity, respectively, depending on different tau substrates used. The increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients. Moreover, analysis of the end products of skin-tau SAA confirmed that the increased seeding activity is accompanied with formation of tau aggregates that are of different physicochemical properties determined by the different tau-substrates used. Our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of the skin misfolded tau can serve as an accurate diagnostic biomarker of tauopathies.

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Section: The Stau-sa Of Ad and All Tauopathies Can Be Specifically Di...supporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: The Stau-sa Of Ad and All Tauopathies Can Be Specifically Di...mentioning

confidence: 99%

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Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

Wang,

Wu,

Gerasimenko

et al. 2023

Preprint

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“…Intense and bright anti-p-α-Syn antibody staining was observed in samples obtained from PD patients, whereas no p-α-Syn antibody staining was observed in samples obtained from healthy individuals. 44 Finally, according to the immuno uorescence staining results obtained with these two antibodies, we successfully constructed a cell model of α-Syn pathological aggregation, and at the same time, we found the appearance of α-Syn pathological aggregation 12 h after induction.…”

Section: Discussionmentioning

confidence: 93%

MAPKAPK2, a dynamic network biomarker of α-synuclein before its aggregation, was significantly highly expressed in both the brain and peripheral blood of PD patients

Ling

Zhong

et al. 2022

Preprint

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One of the important pathological features of Parkinson's disease (PD) is the pathological aggregation of α-synuclein (α-Syn) in the substantia nigra. Preventing the aggregation of α-Syn has become a potential strategy for treating PD. However, the molecular mechanism of α-Syn aggregation is unclear. In this study, using the dynamic network biomarker (DNB) method, we first identified the critical time point when α-Syn undergoes pathological aggregation based on a SH-SY5Y cell model and found that DNB genes encode transcription factors that regulated target genes that were differentially expressed. Interestingly, we found that these DNB genes and their neighbouring genes were significantly enriched in the cellular senescence pathway and thus proposed that the DNB genes HSF1 and MAPKAPK2 regulate the expression of the neighbouring gene SERPINE1. Notably, in GEO data obtained from substantia nigra, prefrontal cortex and peripheral blood samples, the expression level of MAPKAPK2 was significantly higher in PD patients than in healthy people, suggesting that MAPKAPK2 is an early diagnostic biomarker of diseases related to pathological aggregation of α-Syn, such as PD. These findings provide new insights into the mechanisms underlying the pathological aggregation of α-Syn.

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“…In fact, α-Syn not only deposits in the CNS of MSA, but also deposits in peripheral nervous system. Zhe Rong et al reported the deposition of phosphorylated α-syn in the Schwann cells (SCs), a kind of peripheral glial cells, of sural nerves in MSA patients ( Rong et al, 2021 ). Donadio et al reported the abnormal deposition of pS129 in cutaneous nerve fibers of MSA patients, mainly in the somatosensory fibers of the subcutaneous plexus ( Donadio et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Alpha-Synuclein species in oral mucosa as potential biomarkers for multiple system atrophy

Zheng

Cai

et al. 2022

Front. Aging Neurosci.

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BackgroundThe definitive diagnosis of Multiple system atrophy (MSA) requires the evidence of abnormal deposition of α-Synuclein (α-Syn) through brain pathology which is unable to achieve in vivo. Deposition of α-Syn is not limited to the central nervous system (CNS), but also extended to peripheral tissues. Detection of pathological α-Syn deposition in extracerebral tissues also contributes to the diagnosis of MSA. We recently reported the increased expressions of α-Syn, phosphorylated α-Synuclein at Ser129 (pS129), and α-Syn aggregates in oral mucosal cells of Parkinson’s disease (PD), which serve as potential biomarkers for PD. To date, little is known about the α-Syn expression pattern in oral mucosa of MSA which is also a synucleinopathy. Here, we intend to investigate whether abnormal α-Syn deposition occurs in oral mucosal cells of MSA, and to determine whether α-Syn, pS129, and α-Syn aggregates in oral mucosa are potential biomarkers for MSA.MethodsThe oral mucosal cells were collected by using cytobrush from 42 MSA patients (23 MSA-P and 19 MSA-C) and 47 age-matched healthy controls (HCs). Immunofluorescence analysis was used to investigate the presence of α-Syn, pS129, and α-Syn aggregates in the oral mucosal cells. Then, the concentrations of α-Syn species in oral mucosa samples were measured using electrochemiluminescence assays.ResultsImmunofluorescence images indicated elevated α-Syn, pS129, and α-Syn aggregates levels in oral mucosal cells of MSA than HCs. The concentrations of three α-Syn species were significantly higher in oral mucosal cells of MSA than HCs (α-Syn, p < 0.001; pS129, p = 0.042; α-Syn aggregates, p < 0.0001). In MSA patients, the oral mucosa α-Syn levels negatively correlated with disease duration (r = −0.398, p = 0.009). The area under curve (AUC) of receiver operating characteristic (ROC) analysis using an integrative model including age, gender, α-Syn, pS129, and α-Syn aggregates for MSA diagnosis was 0.825, with 73.8% sensitivity and 78.7% specificity.ConclusionThe α-Syn levels in oral mucosal cells elevated in patients with MSA, which may be promising biomarkers for MSA.

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Phosphorylated α-synuclein and phosphorylated tau-protein in sural nerves may contribute to differentiate Parkinson’s disease from multiple system atrophy and progressive supranuclear paralysis

Cited by 9 publications

References 30 publications

Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

MAPKAPK2, a dynamic network biomarker of α-synuclein before its aggregation, was significantly highly expressed in both the brain and peripheral blood of PD patients

Alpha-Synuclein species in oral mucosa as potential biomarkers for multiple system atrophy

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