Renalase Overexpression-Mediated Excessive Metabolism of Peripheral Dopamine, DOPAL Accumulation, and α-Synuclein Aggregation in Baroreflex Afferents Contribute to Neuronal Degeneration and Autonomic Dysfunction DOI Creative Commons

Xue Xiong,

Yi Xu, Yan Zhang

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(5), P. 1243 - 1243

Published: May 20, 2025

Background/Objectives: Increasing evidence reveals the likely peripheral etiology of Parkinson’s disease; however, mechanistic insight into α-Synuclein aggregation in periphery remains unclear. This study aimed to explore effect abnormal expression renalase on dopamine metabolism, toxic DOPAL generation, and subsequently, aggregation. Methods: Blood pressure (BP) was monitored while changing body position rats; serum level detected by ELISA; mRNA/protein were determined qRT-PCR/Western blot; measured using HPLC; distribution explored immunostaining; cell viability ultrastructure examined TUNEL electron microscopy, respectively. Results: The results showed that, PD model rats, increased time-dependently with up-regulated gene/protein nodose ganglia, nucleus tractus solitarius, heart; a reduced content also overexpression PC12 cells. Strikingly, orthostatic BP changes observed before behavior rats. Meanwhile, levels time-dependently. Intriguingly, low molecular weight declined coordinately increase higher α-Synuclein. Clear damages at cellular supported notion findings. Notably, aggregation-induced impairment axonal transport function predates neuronal degeneration mediated overexpression. Conclusions: Our demonstrate that metabolism overexpressed promotes DOPAL-induced leads baroreflex afferent early autonomic failure.

Language: Английский

Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis DOI Creative Commons
Samir Abu‐Rumeileh, Leila Motlagh Scholle, Alexander Mensch

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 5, 2025

Blood phosphorylated (p)-tau 181 and p-tau 217 have been proposed as accurate biomarkers of Alzheimer's disease (AD) pathology. However, blood is also elevated in amyotrophic lateral sclerosis (ALS) without a clearly identified source. We measured serum multicentre cohort ALS (n = 152), AD 111) cases controls 99) recruited from four different centres. Further, we investigated the existence both species using immunohistochemistry (IHC) mass spectrometry (MS) muscle biopsies (IHC: n 13, MS: 5) 14, one cohort. Serum were higher patients compared to controls. IHC MS analyses revealed presence controls, with samples showing increased reactivity atrophic fibres. could potentially be used diagnose AD.

Language: Английский

Citations

4
The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases DOI Open Access
Seojin Lee, Gábor G. Kovács

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4269 - 4269

Published: April 12, 2024

Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. Accumulating evidence supports contribution iron disease pathologies, but delineation its pathogenic role yet challenged by complex multiple neurotoxicity mechanisms supporting reciprocal influence between protein pathology. Here, we review major proteinopathy-specific observations four distinct hypotheses: (1) deposition consequence pathology; (2) promotes (3) protects from or hinders (4) pathology contribute parallelly to pathogenesis. an essential element for physiological function, requiring fine balance levels. Understanding disease-related at more intricate systemic level critical advancements chelation therapies.

Language: Английский

Citations

14
Four-Repeat Tau Seeding in the Skin of Patients With Progressive Supranuclear Palsy DOI
Iván Martínez-Valbuena, Maria Carmela Tartaglia, Susan H. Fox

et al.

JAMA Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

This study discusses 4-repeat tau seeding in the skin of patients with progressive supranuclear palsy.

Language: Английский

Citations

6
Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies DOI Creative Commons
Ilaria Linda Dellarole, Elena Vacchi, Iñigo Ruiz‐Barrio

et al.

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: June 15, 2024

Abstract Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin tauopathies patients, we aimed to exploit ultrasensitive seeding activity assay (SAA) assess patients with tauopathies. In this multicentric, case-control study, synucleinopathies were consecutively recruited sex-matched healthy controls (HC). Subjects underwent double 3 mm biopsy cervical area ankle. Skin tau-SAA, using TauK18 TauK19 as reaction substrates for 4R 3R isoforms, score, clinical scales, biochemical morphological characterization SAA end-products evaluated. We analyzed 58 subjects: 24 (18 progressive supranuclear palsy, PSP, 6 corticobasal degeneration, CBD), 20 (14 Parkinson’s disease, PD, multiple system atrophy, MSA), 14 HC. PSP CBD showed higher at both anatomical sites. A greater sensitivity 4R-SAA than 3R-SAA was observed. tau-SAA identified 71% 93% specificity. Accuracy CBD: vs HC / PD (AUC 0.825), while 0.797), MSA (AU 0.778). differences according site. identifies good accuracy can be used implement in-vivo diagnosis diseases. Further peripheral seed may elucidate structure deposits brain.

Language: Английский

Citations

5
Longitudinal evaluation of polyneuropathy in Parkinson’s disease DOI Creative Commons

Eun Hae Kwon,

Antonia Bieber,

Paula Schülken

et al.

Journal of Neurology, Journal Year: 2024, Volume and Issue: 271(9), P. 6136 - 6146

Published: July 26, 2024

Increasing evidence indicates a higher prevalence of polyneuropathy (PNP) in Parkinson's disease (PD). However, the involvement large fiber neuropathy PD still remains poorly understood. Given lack longitudinal data, we investigated course PNP associated with PD.

Language: Английский

Citations

4
Autonomic dysfunction in progressive supranuclear Palsy: A retrospective study DOI Creative Commons
Yichun Wang,

Man-qing Xie,

Dan Xu

et al.

Clinical Parkinsonism & Related Disorders, Journal Year: 2025, Volume and Issue: 12, P. 100310 - 100310

Published: Jan. 1, 2025

This study aims to investigate the characteristics of autonomic dysfunction in progressive supranuclear palsy (PSP) compared Parkinson's disease (PD) and multiple system atrophy-parkinsonian type (MSA-P). We retrospectively reviewed 128 patients who underwent multidisciplinary team (MDT) intervention at Peking Union Medical College Hospital between March 31, 2021, November 22, 2023. A total 16 PSP, 27 MSA-P, 11 PD were included. Autonomic was assessed using SCOPA-AUT scale medical record data, analyzed with IBM SPSS Statistics 26. revealed varying degrees across all groups. The score lower PSP (16.88 ± 6.70) than MSA-P (23.33 8.80) (p = 0.019), but not significantly different from (18.64 9.80). All five subscales affected though significant differences found only urinary control 0.006) storage 0.008) scores MSA-P. Orthostatic hypotension clinically identified 7.7 % 66.7 27.3 patients, a difference < 0.001). Residual urine volume (137.5 [75.5-190.25] mL) higher (34.5 [1.50-60.00] mL, p 0.001) (9.95 [1.13-56.25] Our findings indicate that presents various forms dysfunction, as by SCOPA-AUT, similarities both PD. Objective measures, such orthostatic blood pressure assessments residual ultrasound, can provide additional insights into PSP.

Language: Английский

Citations

0
Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy DOI Creative Commons
Jinguo Wang, Shelley L. Forrest, Sathish Dasari

et al.

Immunobiology, Journal Year: 2025, Volume and Issue: unknown, P. 152892 - 152892

Published: March 1, 2025

Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 polymorphic region with complex linkage patterns that has been implicated several autoimmune neurological disorders. HLA not systematically examined PSP. It unclear whether can interact to induce an mechanism. We evaluated autopsy confirmed PSP cohort (n = 44) compared allele/haplotype frequencies those of the reference group local deceased Canadian donor pool. performed HLA-Tau peptide binding prediction modelling Class II - Tau Peptide interactions. Odds ratio was 2.94 (95 % CI 1.01 8.55; p 0.047) for DQB1*06:01 allele, 2.59 1.39 4.83; 0.0025) narcolepsy-associated haplotype (DRB1*15:01-DQB1*06:02). One patient 4-repeat PSP-type pathology carrier IgLON5-associated (DRB1*10:01-DQB1*05:01). interactions revealed strong-binding peptides but PSP-protofilament fold alleles DQA1*01:02-DQB1*06:02 DQA1*01:03-DQB1*06:01. Our study suggests epitopes within may bind are found subset patients supporting notion pathophysiological component. These findings have implications subtyping stratifying therapies, including targeting immune modulation.

Language: Английский

Citations

0
Renalase Overexpression-Mediated Excessive Metabolism of Peripheral Dopamine, DOPAL Accumulation, and α-Synuclein Aggregation in Baroreflex Afferents Contribute to Neuronal Degeneration and Autonomic Dysfunction DOI Creative Commons

Xue Xiong,

Yi Xu, Yan Zhang

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(5), P. 1243 - 1243

Published: May 20, 2025

Background/Objectives: Increasing evidence reveals the likely peripheral etiology of Parkinson’s disease; however, mechanistic insight into α-Synuclein aggregation in periphery remains unclear. This study aimed to explore effect abnormal expression renalase on dopamine metabolism, toxic DOPAL generation, and subsequently, aggregation. Methods: Blood pressure (BP) was monitored while changing body position rats; serum level detected by ELISA; mRNA/protein were determined qRT-PCR/Western blot; measured using HPLC; distribution explored immunostaining; cell viability ultrastructure examined TUNEL electron microscopy, respectively. Results: The results showed that, PD model rats, increased time-dependently with up-regulated gene/protein nodose ganglia, nucleus tractus solitarius, heart; a reduced content also overexpression PC12 cells. Strikingly, orthostatic BP changes observed before behavior rats. Meanwhile, levels time-dependently. Intriguingly, low molecular weight declined coordinately increase higher α-Synuclein. Clear damages at cellular supported notion findings. Notably, aggregation-induced impairment axonal transport function predates neuronal degeneration mediated overexpression. Conclusions: Our demonstrate that metabolism overexpressed promotes DOPAL-induced leads baroreflex afferent early autonomic failure.

Language: Английский

Citations

0