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  1. AU="Maina, Katherine N"
  2. AU="Jacobson, Bailey"
  3. AU="Johnson, Andrew J"
  4. AU="Yu Deng"
  5. AU="Ruelle, Yannick"
  6. AU="Jacobs, Jonathan L"
  7. AU="Massmann, Amanda K"
  8. AU="Shah, Rohan R"
  9. AU="Coppin, Peter"
  10. AU="Kun, Lyubomyra"
  11. AU="Grauvogel, Tanja Daniela"
  12. AU="Serafim, Ricardo A M"
  13. AU="Urzainqui, Ana"
  14. AU="Navarro, Elisa"
  15. AU="Ibrahim, Tawheeda"
  16. AU="Sonntag, William E"
  17. AU="Tamagawa, Masumi"
  18. AU="Subhan, Fazli"
  19. AU="Parisi, A"
  20. AU="Calisher, C H"
  21. AU="Altaş, İrem"

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  1. Artikel ; Online: Using FRET-Based Biosensor Cells to Study the Seeding Activity of Tau and α-Synuclein.

    Maina, Katherine N / Smet-Nocca, Caroline / Bitan, Gal

    Methods in molecular biology (Clifton, N.J.)

    2022  Band 2551, Seite(n) 125–145

    Abstract: Two fluorescence resonance energy transfer (FRET)-based biosensor cell lines developed several years ago by the Diamond group (University of Texas, Southwestern) have allowed convenient, sensitive, and specific measurement of the intracellular ... ...

    Abstract Two fluorescence resonance energy transfer (FRET)-based biosensor cell lines developed several years ago by the Diamond group (University of Texas, Southwestern) have allowed convenient, sensitive, and specific measurement of the intracellular aggregation of tau and α-synuclein following the addition of oligomer or small-aggregate "seeds" of these proteins from various sources, and an advancement relative to similar single-fluorophore systems. These biosensor cell lines allow researchers to both visualize the intracellular aggregates of tau or α-synuclein and measure intracellular aggregation with high sensitivity using a FRET signal in flow cytometry. Here we provide detailed protocols for generating seeds, culturing the biosensor cells, measuring intracellular aggregates by flow cytometry, and analyzing the results and discuss the utility of the technique with the aim of characterizing factors involved in the regulation of intracellular tau and α-synuclein aggregation.
    Mesh-Begriff(e) alpha-Synuclein/metabolism ; Fluorescence Resonance Energy Transfer ; tau Proteins/metabolism ; Biosensing Techniques ; Flow Cytometry/methods
    Chemische Substanzen alpha-Synuclein ; tau Proteins
    Sprache Englisch
    Erscheinungsdatum 2022-10-30
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2597-2_10
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis.

    Palma, Jose-Alberto / Martinez, Jose / Millar Vernetti, Patricio / Ma, Thong / Perez, Miguel A / Zhong, Judy / Qian, Yingzhi / Dutta, Suman / Maina, Katherine N / Siddique, Ibrar / Bitan, Gal / Ades-Aron, Benjamin / Shepherd, Timothy M / Kang, Un J / Kaufmann, Horacio

    Movement disorders : official journal of the Movement Disorder Society

    2022  Band 37, Heft 4, Seite(n) 778–789

    Abstract: Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated ...

    Abstract Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models.
    Objective: To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants.
    Methods: Randomized, double-blind, parallel group, placebo-controlled clinical trial at the New York University of patients with probable MSA randomly assigned (3:1) to sirolimus (2-6 mg daily) for 48 weeks or placebo. Primary endpoint was change in the Unified MSA Rating Scale (UMSARS) total score from baseline to 48 weeks. (ClinicalTrials.gov NCT03589976).
    Results: The trial was stopped after a pre-planned interim analysis met futility criteria. Between August 15, 2018 and November 15, 2020, 54 participants were screened, and 47 enrolled and randomly assigned (35 sirolimus, 12 placebo). Of those randomized, 34 were included in the intention-to-treat analysis. There was no difference in change from baseline to week 48 between the sirolimus and placebo in UMSARS total score (mean difference, 2.66; 95% CI, -7.35-6.91; P = 0.648). There was no difference in UMSARS-1 and UMSARS-2 scores either. UMSARS scores changes were similar to those reported in natural history studies. Neuroimaging and blood biomarker results were similar in the sirolimus and placebo groups. Adverse events were more frequent with sirolimus. Analysis of 1-year biomarker trajectories in all participants showed that increases in blood neurofilament light chain (NfL) and reductions in whole brain volume correlated best with UMSARS progression.
    Conclusions: Sirolimus for 48 weeks was futile to slow the progression of MSA and had no effect on biomarkers compared to placebo. One-year change in blood NfL and whole brain atrophy are promising biomarkers of disease progression for future clinical trials. © 2022 International Parkinson and Movement Disorder Society.
    Mesh-Begriff(e) Double-Blind Method ; Humans ; Medical Futility ; Multiple System Atrophy/drug therapy ; Sirolimus/pharmacology ; Sirolimus/therapeutic use ; TOR Serine-Threonine Kinases ; Treatment Outcome ; alpha-Synuclein
    Chemische Substanzen alpha-Synuclein ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
    Sprache Englisch
    Erscheinungsdatum 2022-01-18
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
    ZDB-ID 607633-6
    ISSN 1531-8257 ; 0885-3185
    ISSN (online) 1531-8257
    ISSN 0885-3185
    DOI 10.1002/mds.28923
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Exosomal tau with seeding activity is released from Alzheimer's disease synapses, and seeding potential is associated with amyloid beta.

    Miyoshi, Emily / Bilousova, Tina / Melnik, Mikhail / Fakhrutdinov, Danyl / Poon, Wayne W / Vinters, Harry V / Miller, Carol A / Corrada, Maria / Kawas, Claudia / Bohannan, Ryan / Caraway, Chad / Elias, Chris / Maina, Katherine N / Campagna, Jesus J / John, Varghese / Gylys, Karen Hoppens

    Laboratory investigation; a journal of technical methods and pathology

    2021  Band 101, Heft 12, Seite(n) 1605–1617

    Abstract: Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, ... ...

    Abstract Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, but not all tau is exosomal. The present experiments use a novel flow cytometry assay to quantify depolarization of synaptosomes by KCl after loading with FM2-10, which induces a fluorescence reduction associated with synaptic vesicle release; the degree of reduction in cryopreserved human samples equaled that seen in fresh mouse synaptosomes. Depolarization induced the release of vesicles in the size range of exosomes, along with tetraspanin markers of extracellular vesicles. A number of tau peptides were released, including tau oligomers; released tau was primarily unphosphorylated and C-terminal truncated, with Aβ release just above background. When exosomes were immunopurified from release supernatants, a prominent tau band showed a dark smeared appearance of SDS-stable oligomers along with the exosomal marker syntenin-1, and these exosomes induced aggregation in the HEK tau biosensor assay. However, the flow-through did not seed aggregation. Size exclusion chromatography of purified released exosomes shows faint signals from tau in the same fractions that show a CD63 band, an exosomal size signal, and seeding activity. Crude synaptosomes from control, tauopathy, and AD cases demonstrated lower seeding in tauopathy compared to AD that is correlated with the measured Aβ42 level. These results show that AD synapses release exosomal tau that is C-terminal-truncated, oligomeric, and with seeding activity that is enhanced by Aβ. Taken together with previous findings, these results are consistent with a direct prion-like heterotypic seeding of tau by Aβ within synaptic terminals, with subsequent loading of aggregated tau onto exosomes that are released and competent for tau seeding activity.
    Mesh-Begriff(e) Aged ; Aged, 80 and over ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Cerebral Cortex/metabolism ; Cerebral Cortex/pathology ; Extracellular Vesicles/metabolism ; Female ; Humans ; Male ; Mice ; Middle Aged ; Protein Aggregation, Pathological ; Synapses/metabolism ; Synaptosomes/metabolism ; tau Proteins/metabolism
    Chemische Substanzen Amyloid beta-Peptides ; tau Proteins
    Sprache Englisch
    Erscheinungsdatum 2021-08-30
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80178-1
    ISSN 1530-0307 ; 0023-6837
    ISSN (online) 1530-0307
    ISSN 0023-6837
    DOI 10.1038/s41374-021-00644-z
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Ud II Zs.164: Hefte anzeigen Standort:
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  4. Artikel ; Online: Correction to: α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy.

    Dutta, Suman / Hornung, Simon / Kruayatidee, Adira / Maina, Katherine N / Del Rosario, Irish / Paul, Kimberly C / Wong, Darice Y / Duarte Folle, Aline / Markovic, Daniela / Palma, Jose-Alberto / Serrano, Geidy E / Adler, Charles H / Perlman, Susan L / Poon, Wayne W / Kang, Un Jung / Alcalay, Roy N / Sklerov, Miriam / Gylys, Karen H / Kaufmann, Horacio /
    Fogel, Brent L / Bronstein, Jeff M / Ritz, Beate / Bitan, Gal

    Acta neuropathologica

    2021  Band 142, Heft 3, Seite(n) 513

    Sprache Englisch
    Erscheinungsdatum 2021-05-24
    Erscheinungsland Germany
    Dokumenttyp Published Erratum
    ZDB-ID 1079-0
    ISSN 1432-0533 ; 0001-6322
    ISSN (online) 1432-0533
    ISSN 0001-6322
    DOI 10.1007/s00401-021-02332-0
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy.

    Dutta, Suman / Hornung, Simon / Kruayatidee, Adira / Maina, Katherine N / Del Rosario, Irish / Paul, Kimberly C / Wong, Darice Y / Duarte Folle, Aline / Markovic, Daniela / Palma, Jose-Alberto / Serrano, Geidy E / Adler, Charles H / Perlman, Susan L / Poon, Wayne W / Kang, Un Jung / Alcalay, Roy N / Sklerov, Miriam / Gylys, Karen H / Kaufmann, Horacio /
    Fogel, Brent L / Bronstein, Jeff M / Ritz, Beate / Bitan, Gal

    Acta neuropathologica

    2021  Band 142, Heft 3, Seite(n) 495–511

    Abstract: The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes ... ...

    Abstract The diagnosis of Parkinson's disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain's biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.
    Mesh-Begriff(e) Adult ; Aged ; Aged, 80 and over ; Area Under Curve ; Biomarkers ; Cohort Studies ; Diagnosis, Differential ; Enzyme-Linked Immunosorbent Assay ; Exosomes/immunology ; Female ; Healthy Volunteers ; Humans ; Immunoprecipitation ; Male ; Middle Aged ; Multiple System Atrophy/blood ; Multiple System Atrophy/diagnosis ; Neurons/metabolism ; Oligodendroglia/metabolism ; Parkinson Disease/blood ; Parkinson Disease/diagnosis ; Reproducibility of Results ; Sensitivity and Specificity ; alpha-Synuclein/immunology
    Chemische Substanzen Biomarkers ; SNCA protein, human ; alpha-Synuclein
    Sprache Englisch
    Erscheinungsdatum 2021-05-15
    Erscheinungsland Germany
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1079-0
    ISSN 1432-0533 ; 0001-6322
    ISSN (online) 1432-0533
    ISSN 0001-6322
    DOI 10.1007/s00401-021-02324-0
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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