Potential two‐step proteomic signature for Parkinson's disease: Pilot analysis in the Harvard Biomarkers Study

O’Bryant, Sid; Edwards, Melissa; Zhang, Fan; Johnson, Leigh; Hall, James; Kuras, Yuliya I.; Scherzer, Clemens R.

doi:10.1016/j.dadm.2019.03.001

Cited by 21 publications

(28 citation statements)

References 52 publications

(75 reference statements)

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“…Our results are consistent with the knowledge that XDP is a disease of basal ganglia neurodegeneration 1‐4,9 . This adds XDP to the list of atypical parkinsonian syndromes with increased plasma NfL 24,29,30 …”

Section: Discussionsupporting

confidence: 92%

“…[1][2][3][4]9 This adds XDP to the list of atypical parkinsonian syndromes with increased plasma NfL. 24,29,30 Although NfL may be a nonspecific biomarker of neurodegeneration in XDP, it may still be useful in monitoring disease onset and progression in presymptomatic and symptomatic patients under therapeutic treatment. TAF1 dysregulation acts as a disease-specific biomarker that makes it an attractive readout for target engagement by new therapies, particularly those targeting TAF1 expression and splicing regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Through the development of a highly sensitive fourth‐generation single molecule array, SiMoA (Quanterix Corporation, Billerica, MA), for detection in blood, 27,28 NfL has been reported in different neurodegenerative diseases as a blood‐based biomarker correlating with disease status, progression, and outcomes in different neurological diseases 23,28 . Specifically, it has been shown to be useful in the differential diagnoses of parkinsonian disorders 24,29,30 …”

mentioning

confidence: 99%

“…23,28 Specifically, it has been shown to be useful in the differential diagnoses of parkinsonian disorders. 24,29,30 Clinically, XDP is diagnosed in patients with signs of dystonia and parkinsonism who have a positive history of affected relatives and maternal ancestry from Panay island. 2 Cell-based and biofluid-based disease-specific biomarkers will be needed to understand disease mechanisms, predict progression, and serve as noninvasive readouts for novel therapeutics.…”

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confidence: 99%

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TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X‐linked Dystonia‐Parkinsonism

et al. 2020

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Background X‐linked dystonia‐parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full‐length mRNA transcript. Objectives The objective of this study was to discover cell‐based and biofluid‐based biomarkers for X‐linked dystonia‐parkinsonism. Methods RNA from patient‐derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet‐digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5′ and 3′ to the retrotransposon insertion and the disease‐specific splice variant TAF1‐32i in whole‐blood RNA. Plasma levels of neurofilament light chain were measured using single‐molecule array. Results In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1‐3′/5′ ratio was lower in patient samples, whereas TAF1‐32i expression is higher relative to controls. In whole‐blood RNA, both TAF1‐3′/5′ ratio and TAF1‐32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79. Conclusions TAF1 dysregulation in blood serves as a disease‐specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X‐linked Dystonia‐Parkinsonism

et al. 2020

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“…α-synuclein is associated with FABPs as well as fatty acids and promotes protein aggregation [ 11 , 12 , 13 ]. Furthermore, FABP3 is an expected biomarker for Parkinson’s disease because it increases in the patients’ plasma [ 14 , 15 , 16 ]. Thus, the involvement of FABP3 in the etiology of Parkinson’s disease and unveiling its mechanism are anticipated to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons

et al. 2021

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α-synuclein accumulation into dopaminergic neurons is a pathological hallmark of Parkinson’s disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake and propagation to accumulate in dopaminergic neurons. FABP3 is abundant in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D2L). Here, we investigated the importance of dopamine D2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D2L−/−, dopamine D2 receptor null (D2 null), FABP3−/−, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D2L receptors are co-localized with FABP3. Immunocytochemistry revealed that TH+ D2L−/− or D2 null neurons do not take up α-synuclein monomers. The deletion of α-synuclein C-terminus completely abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1 knockdown also abolished the uptake. D2L and FABP3 were also critical for α-synuclein fibrils uptake. D2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D2L with a caveola structure coupled with FABP3 is critical for α-synuclein uptake by dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including Parkinson’s disease.

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A blood screening tool for detecting mild cognitive impairment and Alzheimer's disease among community‐dwelling Mexican Americans and non‐Hispanic Whites: A method for increasing representation of diverse populations in clinical research

O’Bryant

Zhang

Petersen

et al. 2021

Alzheimer's & Dementia

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Introduction: Representation of Mexican Americans in Alzheimer's disease (AD) clinical research has been extremely poor. Methods: Data were examined from the ongoing community-based, multi-ethnic Health & Aging Brain among Latino Elders (HABLE) study. Participants underwent functional exams, clinical labs, neuropsychological testing, and 3T magnetic resonance imaging of the brain. Fasting proteomic markers were examined for predicting mild cognitive impairment (MCI) and AD using support vector machine models.Results: Data were examined from n = 1649 participants (Mexican American n = 866; non-Hispanic White n = 783). Proteomic profiles were highly accurate in detecting MCI (area under the curve [AUC] = 0.91) and dementia (AUC = 0.95). The proteomic profiles varied significantly between ethnic groups and disease state. Negative predictive value was excellent for ruling out MCI and dementia across ethnic groups.

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Potential two‐step proteomic signature for Parkinson's disease: Pilot analysis in the Harvard Biomarkers Study

Cited by 21 publications

References 52 publications

TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X‐linked Dystonia‐Parkinsonism

TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X‐linked Dystonia‐Parkinsonism

Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons

A blood screening tool for detecting mild cognitive impairment and Alzheimer's disease among community‐dwelling Mexican Americans and non‐Hispanic Whites: A method for increasing representation of diverse populations in clinical research

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