Emerging urinary alpha-synuclein and miRNA biomarkers in Parkinson’s disease

Giri, Banabihari; Seamon, Marissa; Banerjee, Aditi; Chauhan, Sneha; Purohit, Sharad; Morgan, John C.; Baban, Babak; Wakade, Chandramohan

doi:10.1007/s11011-021-00735-2

Cited by 9 publications

(6 citation statements)

References 101 publications

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“…114,115 aSyn has also been assessed in saliva and urine, but the diagnostic value of these biological specimens for aSyn remains uncertain. [116][117][118] The presence of aSyn in EVs was first reported by Lee and colleagues 119 followed by the characterization of those vesicles as EVs and the importance of this finding in aSyn spread and pathology. 120,121 Using specific neuronal markers like L1CAM, it became clear that a portion of aSyn can be released from the CNS via the BBB to the blood and other peripheral biofluids.…”

Section: Discussionmentioning

confidence: 94%

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Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta‐Analysis

Xylaki¹,

Chopra²,

Weber³

et al. 2023

Movement Disorders

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Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development. Proteins and molecular material from any organ, including the central nervous system, can be packed into EVs and transported to the periphery into easily obtainable biological specimens like blood, urine, and saliva. We performed a systematic review and meta‐analysis of articles (published before November 15, 2022) reporting biomarker assessment in EVs in PD patients and healthy controls (HCs). Biomarkers were analyzed using random effects meta‐analysis and the calculated standardized mean difference (Std.MD). Several proteins and ribonucleic acids have been identified in EVs in PD patients, but only α‐synuclein (aSyn) and leucine‐rich repeat kinase 2 (LRRK2) were reported in sufficient studies (n = 24 and 6, respectively) to perform a meta‐analysis. EV aSyn was significantly increased in neuronal L1 cell adhesion molecule (L1CAM)–positive blood EVs in PD patients compared to HCs (Std.MD = 1.84, 95% confidence interval = 0.76–2.93, P = 0.0009). Further analysis of the biological sample and EV isolation method indicated that L1CAM‐IP (immunoprecipitation) directly from plasma was the best isolation method for assessing aSyn in PD patients. Upcoming neuroprotective clinical trials immediately need peripheral biomarkers for identifying individuals at risk of developing PD. Overall, the improved sensitivity of assays means they can identify biomarkers in blood that reflect changes in the brain. CNS‐derived EVs in blood will likely play a major role in biomarker development in the coming years. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 94%

“…This can be attributed to the fact that aSyn in the blood can originate from the aSyn‐rich red blood cells or any peripheral tissue 114,115 . aSyn has also been assessed in saliva and urine, but the diagnostic value of these biological specimens for aSyn remains uncertain 116‐118 …”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta‐Analysis

Xylaki¹,

Chopra²,

Weber³

et al. 2023

Movement Disorders

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“…In addition to the above biomarkers, plasma biomarkers of AD include β -amyloid in plasma, Apolipoprotein E (ApoE), Apolipoprotein J (APOJ), and APP in platelets [ 34 ]. The urine biomarker for AD is AD-associated neurofilament protein (AD7C NTP) [ 35 ]. Other AD biomarkers include advanced glycation end products (AGEs) and isoprostaglandins (IP) [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Feasibility of Using Magnetic Resonance Spectroscopy Test Biomarkers to Diagnose Alzheimer's Disease: Systematic Evaluation and Meta-Analysis

Wei,

Xu,

et al. 2024

Actas Esp Psiquiatr

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Background: Alzheimer's disease (AD) is the leading cause of dementia, resulting in impairments in memory, cognition, decision-making, and social skills. Thus, accurate preclinical diagnosis of Alzheimer's disease is paramount. The identification of biomarkers for Alzheimer's disease through magnetic resonance spectroscopy (MRS) represents a novel adjunctive diagnostic approach. Objective: This study conducted a meta-analysis of the diagnostic results of this technology to explore its feasibility and accuracy. Methods: PubMed, Cochrane Library, EMBASE, and Web of Science databases were searched without restrictions, with the search period extending up to July 31, 2022. The search strategy employed a combination of subject headings and keywords. All retrieved documents underwent screening by two researchers, who selected them for meta-analysis. The included literature was analyzed using Review Manager 5.4 software, with corresponding bias maps, forest plots, and summary receiver operating characteristic (SROC) curves generated and analyzed. Results: A total of 344 articles were retrieved initially, with 11 articles meeting the criteria for inclusion in the analysis. The analysis encompassed data from approximately 1766 patients. In the forest plot, both sensitivity (95% CI) and specificity (95% CI) approached 1. Examining the true positive rate, false positive rate, true negative rate, and false negative rate, all studies on the summary receiver operating characteristic (SROC) curve clustered in the upper left quadrant, suggesting a very high accuracy of biomarkers detected by MRS for diagnosing Alzheimer's disease. Conclusion: The detection of biomarkers by MRS demonstrates feasibility and high accuracy in diagnosing AD. This technology holds promise for widespread adoption in the clinical diagnosis of AD in the future.

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“…Our results also show that differential expression of MALAT1, miR-23b-3p, and α -synuclein is associated with dopaminergic neuronal cell injury and that dopaminergic neuronal cell injury results in the accumulation of large amounts of α -synuclein protein. Therefore, the evaluation of these molecules in urine in free form or associated with extracellular vesicles in biological fluids may lead to early biomarkers for clinical diagnosis [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…One study has demonstrated that circulating miRNAs in plasma, serum, or serum exosomes are potential biomarkers for PD diagnosis. Moreover, it has been found that α -synuclein and miRNA are overexpressed in PD, AD, and dementia [ 20 ]. miR-23b-3p can directly target and regulate the expression of α -synuclein, leading to the development of PD [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

MALAT1 Mediates α-Synuclein Expression through miR-23b-3p to Induce Autophagic Impairment and the Inflammatory Response in Microglia to Promote Apoptosis in Dopaminergic Neuronal Cells

Geng

Zou

et al. 2023

Mediators of Inflammation

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Background. Parkinson’s disease (PD) is a very common neurodegenerative disease that adversely affects the physical and mental health of many patients, but there is currently no effective treatment. Objective. To this end, this study focused on investigating the potential mechanisms leading to dopaminergic neuronal apoptosis in PD. Methods. Rotenone induces damage in dopaminergic neuronal MN9D cells. Apoptosis was detected by flow cytometry, and the expression of apoptosis-related proteins was detected by western blot. RT-qPCR was used to detect the expression of MALAT1 and miR-23b-3p. The expression of α-synuclein was detected by ELISA. A dual luciferase gene reporter assay was used to determine the targeted regulatory relationship between MALAT1 and miR-23b-3p and miR-23b-3p and α-synuclein. MN9D supernatant was cocultured with BV-2 cells, or BV-2 cells were treated with exogenous α-synuclein and then treated with an autophagy inhibitor (3-MA) and autophagy activator (RAPA). The expression of α-synuclein in BV-2 cells was detected by immunofluorescence. The expression of MIP-1α, a marker of microglial activation, was detected by ELISA. The nuclear translocation of NF-κB p65 was detected by immunofluorescence. The expression of proinflammatory cytokines was detected by ELISA. Western blotting was used to detect the expression of autophagy-related proteins. Apoptosis of MN9D cells was detected after coculture of BV-2 supernatant with MN9D. Results. The expression of MALAT1 and α-synuclein was upregulated, while the expression of miR-23b-3p was downregulated in damaged MN9D cells, resulting in cell apoptosis. MALAT1 can negatively regulate the expression of miR-23b-3p, while miR-23b-3p negatively regulates the expression of α-synuclein. α-synuclein can enter BV-2 cells through cell phagocytosis. Coculture of BV-2 cells with α-synuclein or with MN9D supernatant overexpressing MALAT1 resulted in a decrease in the autophagy level of BV-2 cells and an inflammatory reaction. However, miR-23b-3p mimics and knockdown of α-synuclein reversed the effect of MALAT1 on autophagy and the inflammatory response of BV-2 cells. In addition, after coculture of BV-2 cells with α-synuclein, the level of autophagy further decreased when 3-MA was added, while the opposite result occurred when RAPA was added. After coculture of α-synuclein-treated BV-2 cell supernatant with MN9D cells, autophagy-impaired BV-2 promoted the apoptosis of MN9D cells, and 3-MA aggravated the autophagy disorder of BV-2 and further promoted the apoptosis of MN9D cells, while RAPA reversed the autophagy disorder of BV-2 and alleviated the apoptosis of MN9D cells. Conclusion. MALAT1 can promote α-synuclein expression by regulating miR-23b-3p, thereby inducing microglial autophagy disorder and an inflammatory response leading to apoptosis of dopaminergic neurons. This newly discovered molecular mechanism may provide a potential target for the treatment of PD.

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Emerging urinary alpha-synuclein and miRNA biomarkers in Parkinson’s disease

Cited by 9 publications

References 101 publications

Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta‐Analysis

Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta‐Analysis

Feasibility of Using Magnetic Resonance Spectroscopy Test Biomarkers to Diagnose Alzheimer's Disease: Systematic Evaluation and Meta-Analysis

MALAT1 Mediates α-Synuclein Expression through miR-23b-3p to Induce Autophagic Impairment and the Inflammatory Response in Microglia to Promote Apoptosis in Dopaminergic Neuronal Cells

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