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1. Clinical Meaningfulness in Alzheimer’s Disease Clinical Trials. A Report from the EU-US CTAD Task Force

Author

Angioni, D., Cummings, J., Lansdall, C. J., Middleton, L., Sampaio, C., Gauthier, S., Cohen, S., Petersen, R. C., Rentz, D. M., Wessels, A. M., Hendrix, S. B., Jessen, F., Carrillo, M. C., Doody, R. S., Irizarry, M., Andrews, J. S., Vellas, B., Aisen, P., Andrieu, Sandrine, Bateman, Randall, Batrla, Richard, Bell, Joanne, Bosson, Oskar, Bozeat, Sasha, Brooks, Dawn, Haeberlein, Samantha Budd, Buracchio, Teresa, Cho, Min, Choung, Matthew, Cook, Gavin, Crisitello, Darrin, Dangond, Fernando, de Santi, Susan, Dennehy, Ellen, Dhadda, Shobha, Dhillon, Harjeet, Dunn, Billy, Egan, Michael, Elwood, Fiona, Eriksson, Sven, Fagan, Tom, Fillit, Howard, Freskgard, Per-Ola, Gallagher, Diana, Gangi, Gopi, Granda, Carlos, Greeley, David, Gronblad, Anna-Kaija, Hampel, Harald, Hawthorne, Paul, Henley, David, Herring, Joe, Hersch, Steve, Holt, Bill, Iwatsubo, Takeshi, Jones, Daryl, Kahl, Anja, Kinney, Gene, Kolb, Hartmuth, Kramer, Lynn, Kulic, Luka, Kumar, Sanjay, Lannfelt, Lars, Lawson, John, Legrand, Valérie, Lenington, Rachel, Longo, Frank, Matthews, Brandy, Masterman, Donna, McLinden, Kristina, Mikels, Sarah, Miller, Michael, Mintun, Mark, Moebius, Hans, Monteiro, Cecilia, Morken, Mario, Murphy, Jennifer, Odergren, Tomas, Osswald, Gunilla, Parnas, Laura, Patru, Maria-Magdalena, Prazma, Charlene, Raman, Rema, Reyderman, Larisa, Rogers, Sharon, Roman, Lise, Romano, Gary, Roskey, Mark, Rubino, Ivana, Ryan, Laurie, Salloway, Stephen, Schindler, Rachel, Schneider, Lon, Scott, David, Sims, John, Skovronsky, Daniel, Soto, Marion, Sperling, Reisa, Steukers, Lennert, Stoops, Erik, Strittmatter, Stephen, Tahami, Amir, Tamagnan, Gilles, Tariot, Gilles, Toloue, Masoud, Touchon, Jacques, Vanmechelen, Eugeen, Walt, Len, Weinberg, Mark, Weiner, Michael, White, Anne, Wiesel, Iris, Wilson, David, Yarenis, Lisa, Zago, Wagner, and Zhou, Jin

Published
2024
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2. Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force

Author

Soto, Maria, Rosenberg, P., Ballard, C., Vellas, B., Miller, D., Gauthier, S., Carrillo, M. C., Lyketsos, C., Ismail, Z., Abushakra, Susan, Afshar, Mohammad, Agus, Sam, Aiden, Paul, Alam, John, Algeciras-Schimnich, Alicia, Andrieu, Sandrine, Baruch, Amos, Bateman, Randall, Batrla, Richard, Baudler, Monika, Bell, Joanne, Bittner, Tobias, Bozeat, Sasha, Braunstein, Joel, Brooks, Dawn, Brooks, Tricia, Bullain, Szofia, Burmeister, Jan, Carrillo, Maria, Cho, Min, Collins, Emily, Cook, Gavin, Dague, Chris, De Santi, Susan, Doody, Rachelle, Dunn, Billy, Egan, Michael, Eriksson, Sven, Esquivel, Rianne, Fagan, Tom, Ferrell, Phyllis, Fillit, Howard, Gallagher, Michela, Grönblad, Anna-Kaija, Hains, Avis, Hampel, Harald, Hansson, Oskar, Hefting, Nanco, Hendrix, Suzanne, Ho, Carole, Hu, Helen, Jones, Daryl, Kinney, Gene, Kinnon, Paul, Kurzman, Ricky, Lannfelt, Lars, Lawson, John, LeBastard, Nathalie, Legrand, Valérie, Lewandowski, Nicole, Lim, Carine, Masterman, Donna, Masters, Colin, Lu, Ming, Mintun, Mark, Molinuevo, José Luis, Monteiro, Cecilia, Navia, Bradford, Odergren, Tomas, Osswald, Gunilla, Penny, Lewis, Pontecorvo, Michael, Porsteinsson, Anton, Rabe, Christine, Raman, Rema, Respondek, Gesine, Reyderman, Larisa, Rogers, Sharon, Rosenberg, Paul, Rosenzweig-Lipson, Sharon, Roskey, Mark, Carrie, Rubel, Saad, Ziad, Salloway, Stephen, Schindler, Rachel, Selkoe, Dennis, Shulman, Melanie, Sims, John, Sink, Kaycee, Sipe, Lisa, Skovronsky, Daniel, Somers, Elizabeth, Streffer, Johannes, Such, Pedro, Suhy, Joyce, Toloue, Masoud, Touchon, Jacques, Vandijck, Manu, Weiner, Michael, White, Anne, Wilson, David, Zago, Wagner, and Zhou, Jin

Published
2024
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3. Can We Use Blood Biomarkers as Entry Criteria and for Monitoring Drug Treatment Effects in Clinical Trials? A Report from the EU/US CTAD Task Force

Author

Angioni, D., Hansson, O., Bateman, R. J., Rabe, C., Toloue, M., Braunstein, J. B., Agus, S., Sims, J. R., Bittner, T., Carrillo, M. C., Fillit, H., Masters, C. L., Salloway, S., Aisen, P., Weiner, M., Vellas, B., Gauthier, S., Abushakra, Susan, Afshar, Mohammad, Alam, John, Algeciras-Schimnich, Alicia, Andrieu, Sandrine, Ballard, Clive, Baruch, Amos, Batrla, Richard, Baudler, Monika, Bell, Joanne, Bozeat, Sasha, Brooks, Dawn, Brooks, Tricia, Bullain, Szofia, Burmeister, Jan, Cho, Min, Collins, Emily, Cook, Gavin, Cummings, Jeffrey, Dague, Chris, De Santi, Susan, Doody, Rachelle, Dunn, Billy, Egan, Michael, Eriksson, Sven, Esquivel, Rianne, Fagan, Tom, Ferrell, Phyllis, Gallagher, Michela, Grönblad, Anna-Kaija, Hains, Avis, Hampel, Harald, Hefting, Nanco, Hendrix, Suzanne, Ho, Carole, Hu, Helen, Ismail, Zahinoor, Jones, Daryl, Kinney, Gene, Kinnon, Paul, Kurzman, Ricky, Lannfelt, Lars, Lawson, John, LeBastard, Nathalie, Legrand, Valérie, Lewandowski, Nicole, Lim, Carine, Lyketsos, Costantine, Masterman, Donna, Lu, Ming, Mintun, Mark, Molinuevo, José Luis, Monteiro, Cecilia, Navia, Bradford, Odergren, Tomas, Osswald, Gunilla, Penny, Lewis, Pontecorvo, Michael, Porsteinsson, Anton, Raman, Rema, Respondek, Gesine, Reyderman, Larisa, Rogers, Sharon, Rosenberg, Paul, Rosenzweig-Lipson, Sharon, Roskey, Mark, Carrie, Rubel, Saad, Ziad, Schindler, Rachel, Selkoe, Dennis, Shulman, Melanie, Sink, Kaycee, Sipe, Lisa, Skovronsky, Daniel, Somers, Elizabeth, Soto, Maria, Streffer, Johannes, Such, Pedro, Suhy, Joyce, Touchon, Jacques, Vandijck, Manu, White, Anne, Wilson, David, Zago, Wagner, and Zhou, Jin

Published
2023
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4. Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2

Author

Ngolab, Jennifer, Canchi, Saranya, Rasool, Suhail, Elmaarouf, Abderrahman, Thomas, Kimberly, Sarsoza, Floyd, Grundman, Jennifer, Mante, Michael, Florio, Jazmin, Nandankar, Nimisha, Korouri, Shaina, Zago, Wagner, Masliah, Eliezer, and Rissman, Robert A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Ophthalmology and Optometry, Neurosciences, Dementia, Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Genetics, Aging, Eye Disease and Disorders of Vision, Neurodegenerative, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Eye, Neurological, Animals, Caspase 2, Cell Death, Female, Humans, Male, Mice, Mice, Transgenic, Mutation, Protein Isoforms, Retinal Diseases, Retinal Ganglion Cells, Tauopathies, tau Proteins, Retina, Tau, repeat tau, Retinopathy, tauopathy, Alzheimer's, tauopathy, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology
Abstract

The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick's Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma.

Published
2021

5. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data

Author

Pagano, Gennaro, Boess, Frank G, Taylor, Kirsten I, Ricci, Benedicte, Mollenhauer, Brit, Poewe, Werner, Boulay, Anne, Anzures-Cabrera, Judith, Vogt, Annamarie, Marchesi, Maddalena, Post, Anke, Nikolcheva, Tania, Kinney, Gene G, Zago, Wagner M, Ness, Daniel K, Svoboda, Hanno, Britschgi, Markus, Ostrowitzki, Susanne, Simuni, Tanya, Marek, Kenneth, Koller, Martin, Sevigny, Jeff, Doody, Rachelle, Fontoura, Paulo, Umbricht, Daniel, Bonni, Azad, Investigators, PASADENA, Group, Prasinezumab Study, Altendorf, Claudia, Anandan, Chareyna, Andrews, Giulia, Ansquer, Solène, Arrouasse, Raphaele, Aslam, Sana, Azulay, Jean-Philippe, Baker, Jeanette, Martinez, Ernest Balaguer, Barbu, Shadi, Bardram, Kara, Bega, Danny, Marco, Helena Bejr-Kasem, Benatru, Isabelle, Benchetrit, Eve, Bernhard, Felix, Besharat, Amir, Bette, Sagari, Bichon, Amelie, Billnitzer, Andrew, Blondeau, Sophie, Boraud, Thomas, Borngräber, Freiderike, Boyd, James, Brockmann, Kathrin, Brodsky, Matthew, Brown, Ethan, Bruecke, Christof, Calvas, Fabienne, Canelo, Monica, Carbone, Federico, Carroll, Claire, Fernandez, Laura Casado, Cassé-Perrot, Catherine, Castrioto, Anna, Catala, Helene, Chan, Justine, Cheriet, Samia, Ciabarra, Anthony, Classen, Joseph, Coleman, Juliana, Coleman, Robert, Compta, Yaroslau, Corbillé, Anne-Gaëlle, Corvol, Jean-Christophe, Cosgaya, Mariana, Dahodwala, Nabila, Damier, Philippe, David, Elodie, Davis, Thomas, Dean, Marissa, Debilly, Berengere, DeGiorgio, Janell, Deik, Andres, Delaby, Laure, Delfini, Marie-Helene, Derkinderen, Pascal, Derost, Philipp, de Toledo, Maria, Deuel, Lisa, Diaz-Hernandez, Ann Marie, Dietiker, Cameron, Dimenshteyn, Karina, Dotor, Julio, Durif, Franck, Ebentheuer, Jens, Eggert, Karla Maria, Madueño, Sara Eichau, Eickhoff, Claudia, Ellenbogen, Aaron, Ellmerer, Philipp, and Vazquez, Ines Esparragosa

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurodegenerative, Parkinson's Disease, Clinical Research, Neurosciences, Aging, Clinical Trials and Supportive Activities, Brain Disorders, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Neurological, PASADENA Investigators, Prasinezumab Study Group, MDS-UPDRS = Movement Disorder Society—Unified Parkinson's Disease Rating Scale, Parkinson's disease, Phase II clinical trial, alpha-synuclein, disease modification treatments, disease progression, monoclonal antibodies, prasinezumab, Psychology, Clinical sciences, Biological psychology
Abstract

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40-80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve). Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD. Trial Registration: NCT03100149.

Published
2021

7. The mechanism of action, pharmacological characteristics, and clinical utility of the amyloid depleter birtamimab for the potential treatment of AL amyloidosis.

Author

Palladini, Giovanni, Liedtke, Michaela, Zago, Wagner, Dolan, Phil, Kinney, Gene G., and Gertz, Morie A.

Subjects
CARDIAC amyloidosis, AMYLOID, PLASMA cell diseases, AMYLOIDOSIS, CLINICAL trials, PLASMA cells
Abstract

Amyloid light chain (AL) amyloidosis is a progressive plasma cell disorder caused by amyloid deposition resulting in organ damage and failure. Current standard-of-care treatments target clonal plasma cells, the source of misfolded light chains (amyloid precursors), yet only half of patients with advanced disease survive ≥6 months. The amyloid depleter birtamimab is an investigational humanized monoclonal antibody that binds misfolded κ and λ light chains with high specificity and was designed to neutralize soluble toxic light chain aggregates and promote phagocytic clearance of deposited amyloid. Post hoc analyses from the Phase 3 VITAL trial suggested birtamimab plus standard of care confers a survival benefit in patients with advanced (Mayo Stage IV) AL amyloidosis. AFFIRM-AL (NCT04973137), a Phase 3 confirmatory trial of birtamimab plus standard of care in patients with Mayo Stage IV AL amyloidosis, is ongoing. This review summarizes birtamimab's mechanism of action, attributes, and potential clinical utility. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Anti-α-synuclein immunotherapy reduces α-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy

Author

Spencer, Brian, Valera, Elvira, Rockenstein, Edward, Overk, Cassia, Mante, Michael, Adame, Anthony, Zago, Wagner, Seubert, Peter, Barbour, Robin, Schenk, Dale, Games, Dora, Rissman, Robert A, and Masliah, Eliezer

Subjects
Biomedical and Clinical Sciences, Immunology, Biotechnology, Prevention, Brain Disorders, Lewy Body Dementia, Immunization, Neurosciences, Aging, Parkinson's Disease, Vaccine Related, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Neurological, Animals, Antibodies, Monoclonal, Axonal Transport, Axons, Brain, Disease Models, Animal, Female, Functional Laterality, Genetic Vectors, Humans, Immunization, Passive, Lentivirus, Maze Learning, Mice, Transgenic, Neurodegenerative Diseases, alpha-Synuclein, alpha-synuclein, Animal model, Axonal transport, Synucleinopathy, α-synuclein, Biochemistry and Cell Biology, Clinical Sciences, Biochemistry and cell biology
Abstract

Neurodegenerative disorders such as Parkinson's Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are characterized by progressive accumulation of α-synuclein (α-syn) in neurons. Recent studies have proposed that neuron-to-neuron propagation of α-syn plays a role in the pathogenesis of these disorders. We have previously shown that antibodies against the C-terminus of α-syn reduce the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy, probably by abrogating the axonal transport and accumulation of α-syn in in vivo models. Here, we assessed the effect of passive immunization against α-syn in a new mouse model of axonal transport and accumulation of α-syn. For these purpose, non-transgenic, α-syn knock-out and mThy1-α-syn tg (line 61) mice received unilateral intra-cerebral injections with a lentiviral (LV)-α-syn vector construct followed by systemic administration of the monoclonal antibody 1H7 (recognizes amino acids 91-99) or control IgG for 3 months. Cerebral α-syn accumulation and axonopathy was assessed by immunohistochemistry and effects on behavior were assessed by Morris water maze. Unilateral LV-α-syn injection resulted in axonal propagation of α-syn in the contra-lateral site with subsequent behavioral deficits and axonal degeneration. Passive immunization with 1H7 antibody reduced the axonal accumulation of α-syn in the contra-lateral side and ameliorated the behavioral deficits. Together this study supports the notion that immunotherapy might improve the deficits in models of synucleinopathy by reducing the axonal propagation and accumulation of α-syn. This represents a potential new mode of action through which α-syn immunization might work.

Published
2017

9. Binding Characteristics of PRX012 Surrogate Demonstrate Potent Engagement of Toxic Amyloid Beta Protofibrils and Robust Clearance of Pyroglutamate-modified Amyloid Beta (P7-9.003)

Author

Campbell, Brian, primary, Zhang, Gang, additional, Salmans, Joshua, additional, Elmaarouf, Abderrahman, additional, Tam, Stephen, additional, Porat, Amir, additional, Skov, Michael, additional, Dolan, Philip, additional, Kinney, Gene, additional, and Zago, Wagner, additional

Published
2024
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11. Exploratory Sensor-based Outcome Measures Show Divergent Slopes of Motor Sign Progression in Parkinson’s Disease Patients Treated with Prasinezumab

Author

Taylor, Kirsten, primary, Lipsmeier, Florian, additional, Scelsi, Marzia, additional, Volkova-Volkmar, Ekaterina, additional, Rukina, Daria, additional, Popp, Werner, additional, Lambrecht, Stefan, additional, Anzures-Cabrera, Judith, additional, Summers, David, additional, Abt, Markus, additional, Monnet, Annabelle, additional, Kilchenmann, Timothy, additional, Schjodt-Eriksen, Jens, additional, Essioux, Laurent, additional, Kustermann, Thomas, additional, Zago, Wagner, additional, Svoboda, Hanno, additional, Nikolcheva, Tania, additional, Postuma, Ronald, additional, Pagano, Gennaro, additional, and Lindemann, Michael, additional

Published
2024
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12. The subcellular arrangement of alpha-synuclein proteoforms in the Parkinson’s disease brain as revealed by multicolor STED microscopy

Author

Moors, Tim E., Maat, Christina A., Niedieker, Daniel, Mona, Daniel, Petersen, Dennis, Timmermans-Huisman, Evelien, Kole, Jeroen, El-Mashtoly, Samir F., Spycher, Liz, Zago, Wagner, Barbour, Robin, Mundigl, Olaf, Kaluza, Klaus, Huber, Sylwia, Hug, Melanie N., Kremer, Thomas, Ritter, Mirko, Dziadek, Sebastian, Geurts, Jeroen J. G., Gerwert, Klaus, Britschgi, Markus, and van de Berg, Wilma D. J.

Published
2021
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15. Two‐Year observational study of autonomic skin function in patients with Parkinson's disease compared to healthy individuals

Author

Siepmann, Timo, primary, Arndt, Martin, additional, Sedghi, Annahita, additional, Szatmári, Szabolcs, additional, Horváth, Tamás, additional, Takáts, Annamária, additional, Bereczki, Dániel, additional, Moskopp, Mats Leif, additional, Buchmann, Sylvia, additional, Skowronek, Cornelia, additional, Zago, Wagner, additional, Woranush, Warunya, additional, Lapusca, Razvan, additional, Weidemann, Marie Luise, additional, Gibbons, Christopher H., additional, Freeman, Roy, additional, Reichmann, Heinz, additional, Puetz, Volker, additional, Barlinn, Kristian, additional, Pintér, Alexandra, additional, and Illigens, Ben Min‐Woo, additional

Published
2023
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23. Remote monitoring of progression in early Parkinson’s disease: reliability and validity of the Roche PD Mobile Application v2

Author

Lipsmeier, Florian, primary, Taylor, Kirsten I., additional, Postuma, Ronald B., additional, Volkova-Volkmar, Ekaterina, additional, Kilchenmann, Timothy, additional, Mollenhauer, Brit, additional, Bamdadian, Atieh, additional, Popp, Werner L., additional, Cheng, Wei-Yi, additional, Zhang, Yan Ping, additional, Wolf, Detlef, additional, Schjodt-Eriksen, Jens, additional, Boulay, Anne, additional, Svoboda, Hanno, additional, Zago, Wagner, additional, Pagano, Gennaro, additional, and Lindemann, Michael, additional

Published
2021
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24. Systematic Assessment of 10 Biomarker Candidates Focusing on α‐Synuclein‐Related Disorders

Author

Schulz, Isabel, primary, Kruse, Niels, additional, Gera, Roland G., additional, Kremer, Thomas, additional, Cedarbaum, Jesse, additional, Barbour, Robin, additional, Zago, Wagner, additional, Schade, Sebastian, additional, Otte, Birgit, additional, Bartl, Michael, additional, Hutten, Samantha J., additional, Trenkwalder, Claudia, additional, and Mollenhauer, Brit, additional

Published
2021
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25. Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2

Author

Ngolab, Jennifer, primary, Canchi, Saranya, additional, Rasool, Suhail, additional, Elmaarouf, Abderrahman, additional, Thomas, Kimberly, additional, Sarsoza, Floyd, additional, Grundman, Jennifer, additional, Mante, Michael, additional, Florio, Jazmin, additional, Nandankar, Nimisha, additional, Korouri, Shaina, additional, Zago, Wagner, additional, Masliah, Eliezer, additional, and Rissman, Robert A., additional

Published
2021
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26. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction

Author

Lautenschläger, Janin, Stephens, Amberley D., Fusco, Giuliana, Ströhl, Florian, Curry, Nathan, Zacharopoulou, Maria, Michel, Claire H., Laine, Romain, Nespovitaya, Nadezhda, Fantham, Marcus, Pinotsi, Dorothea, Zago, Wagner, Fraser, Paul, Tandon, Anurag, St George-Hyslop, Peter, Rees, Eric, Phillips, Jonathan J., De Simone, Alfonso, Kaminski, Clemens F., Kaminski Schierle, Gabriele S., Stephens, Amberley D [0000-0002-7303-6392], Ströhl, Florian [0000-0002-2603-0780], St George-Hyslop, Peter [0000-0003-0796-7209], Phillips, Jonathan J [0000-0002-5361-9582], Kaminski, Clemens F [0000-0002-5194-0962], Schierle, Gabriele S Kaminski [0000-0002-1843-2202], and Apollo - University of Cambridge Repository

Subjects
animal diseases, Science, Presynaptic Terminals, In Vitro Techniques, Article, Cell Line, Rats, Sprague-Dawley, Protein Aggregates, Microscopy, Electron, Transmission, mental disorders, Animals, Humans, lcsh:Science, Nuclear Magnetic Resonance, Biomolecular, Binding Sites, Lipid Metabolism, Rats, nervous system diseases, nervous system, alpha-Synuclein, lcsh:Q, Calcium, Synaptic Vesicles, Protein Binding, Synaptosomes
Abstract

Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium. Indeed, dSTORM on synaptosomes shows that calcium mediates the localization of alpha-synuclein at the pre-synaptic terminal, and an imbalance in calcium or alpha-synuclein can cause synaptic vesicle clustering, as seen ex vivo and in vitro. This study provides a new view on the binding of alpha-synuclein to synaptic vesicles, which might also affect our understanding of synucleinopathies., Alpha-synuclein is associated with neuronal dysfunction in Parkinson’s disease. This study shows that alpha-synuclein interacts with neuronal synaptic vesicles in a calcium-dependent fashion, and this interaction is important for synaptic vesicle clustering.

Published
2018

27. Immunohistochemical Detection of Synuclein Pathology in Skin in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinsonism

Author

Al‐Qassabi, Ahmed, primary, Tsao, Tsu‐Shuen, additional, Racolta, Adriana, additional, Kremer, Thomas, additional, Cañamero, Marta, additional, Belousov, Anton, additional, Santana, Madison A., additional, Beck, Rachel C., additional, Zhang, Hongjun, additional, Meridew, Jeffrey, additional, Pugh, Judith, additional, Lian, Fangru, additional, Robida, Mark D., additional, Ritter, Mirko, additional, Czech, Christian, additional, Beach, Thomas G., additional, Pestic‐Dragovich, Lidija, additional, Taylor, Kirsten I., additional, Zago, Wagner, additional, Tang, Lei, additional, Dziadek, Sebastian, additional, and Postuma, Ronald B., additional

Published
2020
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30. Detailed structural orchestration of Lewy pathology in Parkinson's disease as revealed by 3D multicolor STED microscopy

Author

Moors, Tim E., Maat, Christina A., Niedieker, Daniel, Mona, Daniel, Petersen, Dennis, Timmermans-Huisman, Evelien, Kole, Jeroen, El-Mashtoly, Samir F., Zago, Wagner, Barbour, Robin, Mundigl, Olaf, Kaluza, Klaus, Huber, Sylwia, Hug, Melanie N., Kremer, Thomas, Ritter, Mirko, Dziadek, Sebastian, Geurts, Jeroen J.G., Gerwert, Klaus, Britschgi, Markus, Berg, Wilma D.J. van de, Anatomy and neurosciences, Amsterdam Neuroscience - Neurodegeneration, and CCA - Imaging and biomarkers

Abstract

Post-translational modifications of alpha-synuclein (aSyn), in particular phosphorylation at Serine 129 (Ser129-p) and truncation of its C-terminus (CTT), have been implicated in Parkinson's disease (PD) pathophysiology. Although great interest has emerged for these species as potential biomarkers and therapeutic targets in PD, little is known about their (sub)cellular manifestation in the human brain. In this study, we mapped distribution patterns of Ser129-p and CTT aSyn in neurons with and without Lewy pathology. The combination of highly selective antibodies with multicolor STED microscopy allowed detailed phenotyping of subcellular neuropathology in PD. Nigral Lewy Bodies revealed an onion skin-like 3D architecture, with a framework of Ser129-p aSyn and neurofilaments encapsulating CTT and membrane-associated aSyn epitopes. Based on the identification of subcellular pathological phenotypes in this study, we present a novel hypothesis for maturation stages of Lewy pathology and provide evidence for a key role for Ser129-p aSyn in Lewy inclusion formation.

Published
2018

31. Subcellular orchestration of alpha-synuclein variants in Parkinson’s disease brains revealed by 3D multicolor STED microscopy

Author

Moors, Tim E., primary, Maat, Christina A., additional, Niedieker, Daniel, additional, Mona, Daniel, additional, Petersen, Dennis, additional, Timmermans-Huisman, Evelien, additional, Kole, Jeroen, additional, El-Mashtoly, Samir F., additional, Spycher, Liz, additional, Zago, Wagner, additional, Barbour, Robin, additional, Mundigl, Olaf, additional, Kaluza, Klaus, additional, Huber, Sylwia, additional, Hug, Melanie N., additional, Kremer, Thomas, additional, Ritter, Mirko, additional, Dziadek, Sebastian, additional, Geurts, Jeroen J.G., additional, Gerwert, Klaus, additional, Britschgi, Markus, additional, and van de Berg, Wilma D.J., additional

Published
2018
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32. Immunohistochemical Detection of Synuclein Pathology in Skin in Idiopathic Rapid Eye Movement Sleep Behavior Disorder and Parkinsonism.

Author

Al‐Qassabi, Ahmed, Tsao, Tsu‐Shuen, Racolta, Adriana, Kremer, Thomas, Cañamero, Marta, Belousov, Anton, Santana, Madison A., Beck, Rachel C., Zhang, Hongjun, Meridew, Jeffrey, Pugh, Judith, Lian, Fangru, Robida, Mark D., Ritter, Mirko, Czech, Christian, Beach, Thomas G., Pestic‐Dragovich, Lidija, Taylor, Kirsten I., Zago, Wagner, and Tang, Lei

Abstract

Background: Recent studies reported abnormal alpha‐synuclein deposition in biopsy‐accessible sites of the peripheral nervous system in Parkinson's disease (PD). This has considerable implications for clinical diagnosis. Moreover, if deposition occurs early, it may enable tissue diagnosis of prodromal PD. Objective: The aim of this study was to develop and test an automated bright‐field immunohistochemical assay of cutaneous pathological alpha‐synuclein deposition in patients with idiopathic rapid eye movement sleep behavior disorder, PD, and atypical parkinsonism and in control subjects. Methods: For assay development, postmortem skin biopsies were taken from 28 patients with autopsy‐confirmed Lewy body disease and 23 control subjects. Biopsies were stained for pathological alpha‐synuclein in automated stainers using a novel dual‐immunohistochemical assay for serine 129‐phosphorylated alpha‐synuclein and pan‐neuronal marker protein gene product 9.5. After validation, single 3‐mm punch skin biopsies were taken from the cervical 8 paravertebral area from 79 subjects (28 idiopathic rapid eye movement sleep behavior disorder, 20 PD, 10 atypical parkinsonism, and 21 control subjects). Raters blinded to clinical diagnosis assessed the biopsies. Results: The immunohistochemistry assay differentiated alpha‐synuclein pathology from nonpathological‐appearing alpha‐synuclein using combined phosphatase and protease treatments. Among autopsy samples, 26 of 28 Lewy body samples and none of the 23 controls were positive. Among living subjects, punch biopsies were positive in 23 (82%) subjects with idiopathic rapid eye movement sleep behavior disorder, 14 (70%) subjects with PD, 2 (20%) subjects with atypical parkinsonism, and none (0%) of the control subjects. After a 3‐year follow‐up, eight idiopathic rapid eye movement sleep behavior disorder subjects phenoconverted to defined neurodegenerative syndromes, in accordance with baseline biopsy results. Conclusion: Even with a single 3‐mm punch biopsy, there is considerable promise for using pathological alpha‐synuclein deposition in skin to diagnose both clinical and prodromal PD. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Published
2021
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33. CROSS-DISEASE CHARACTERIZATION OF ALPHA-SYNUCLEIN PATHOLOGY IN HUMAN POSTMORTEM BRAIN TISSUE USING EPITOPE-SPECIFIC ANTIBODIES

Author

Maat, Christina, Moors, T., R, Barbour, Zago, Wagner, Britschgi, Markus, van de Berg, WDJ, Anatomy and neurosciences, and Amsterdam Neuroscience - Neurodegeneration

Abstract

Synucleinopathies are characterized by the presence of neuronal or glialinclusions, with a large variety of morphologies, containing the protein alpha-synuclein (aSyn). In the brain, aSyn can manifest in many different conformational and post-translationally modified variants. However, at present, little is known about the expression and localization these aSyn species in different synucleinopathies. Therefore, this study characterized the immunoreactivity of epitope-specific antibodies against aSyn’s intact C-terminus, calpain-cleaved, and phosphorylated aSyn in different brain regions of donors with Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, and multiple system atrophy. Immunoreactivity was also characterized in donors with Alzheimer’s disease, progressive supranuclear palsy and age-matched non-demented controls. Revealed morphological structures were scored semi-quantitatively, and compared with the antibody KM51, used for routine diagnostics. Although all utilized antibodies detected Lewy pathology, they showed differences in morphology and the amount of immunoreactive structures. The antibody against phosphorylated aSyn revealed the largest amount and the most extensive palette of morphological structures as compared to the other antibodies in all synucleinopathies. Both the antibody against phosphorylated aSyn and the antibody against calpain-cleaved aSyn visualized substantially more glial pathology than the KM51 antibody. The antibody against the intact C-terminus of aSyn detected Lewy pathology to a lesser extent than the other antibodies, but visualized synaptic-like staining in all synucleinopathiesand non-demented controls. Hence, this antibody may detect wild-type physiological aSyn. In conclusion, epitope-specific antibodies against different aSyn species identify specific sets of morphological structures, indicating that a combination of aSyn antibodies could ameliorate the pathological diagnosis of synucleinopathies.

Published
2017

34. Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson’s Disease (CAPTURE PD): Protocol for a Multicenter Study

Author

Siepmann, Timo, Pintér, Alexandra, Buchmann, Sylvia J., Stibal, Leonie, Arndt, Martin, Kubasch, Anne Sophie, Kubasch, Marie Luise, Penzlin, Ana Isabel, Frenz, Elka, Zago, Wagner, Horváth, Tamás, Szatmári Jr., Szabolcs, Bereczki, Dániel, Takáts, Annamária, Ziemssen, Tjalf, Lipp, Axel, Freeman, Roy, Reichmann, Heinz, Barlinn, Kristian, and Illigens, Ben Min-Woo

Subjects
axon-reflex, autonomic, diagnosis, Parkinson’s disease, ddc:610, Parkinson-Krankheit, autonom, Axon-Reflex, Diagnose, pilomotor, Technische Universität Dresden, Publikationsfonds, Parkinson’s disease, autonomic, axon-reflex, diagnosis, pilomotor, Technische Universität Dresden, Publishing Fund, Protocols, pilomotor, Neuroscience
Abstract

Background In Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function. Methods/design A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation. Discussion We anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD. Clinical trail registration TRN NCT03043768.

Published
2017

36. Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease

Author

Jankovic, Joseph, primary, Goodman, Ira, additional, Safirstein, Beth, additional, Marmon, Tonya K., additional, Schenk, Dale B., additional, Koller, Martin, additional, Zago, Wagner, additional, Ness, Daniel K., additional, Griffith, Sue G., additional, Grundman, Michael, additional, Soto, Jay, additional, Ostrowitzki, Susanne, additional, Boess, Frank G., additional, Martin-Facklam, Meret, additional, Quinn, Joseph F., additional, Isaacson, Stuart H., additional, Omidvar, Omid, additional, Ellenbogen, Aaron, additional, and Kinney, Gene G., additional

Published
2018
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41. 2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis

Author

Renz, Mark, primary, Torres, Ronald, additional, Dolan, Philip J., additional, Tam, Stephen J., additional, Tapia, Jose R., additional, Li, Lauri, additional, Salmans, Joshua R., additional, Barbour, Robin M., additional, Shughrue, Paul J., additional, Nijjar, Tarlochan, additional, Schenk, Dale, additional, Kinney, Gene G., additional, and Zago, Wagner, additional

Published
2016
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42. Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin

Author

Higaki, Jeffrey N., primary, Chakrabartty, Avi, additional, Galant, Natalie J., additional, Hadley, Kevin C., additional, Hammerson, Bradley, additional, Nijjar, Tarlochan, additional, Torres, Ronald, additional, Tapia, Jose R., additional, Salmans, Joshua, additional, Barbour, Robin, additional, Tam, Stephen J., additional, Flanagan, Ken, additional, Zago, Wagner, additional, and Kinney, Gene G., additional

Published
2016
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43. Anti-Mcam Monoclonal Antibody PRX003 Inhibits the Unique Migratory Potential of Pathogenic IL-17–Producing T Cells

Author

Flanagan, Kenneth, primary, Tam, Stephen J., additional, Li, Lauri, additional, Dolan, Philip J., additional, Barbour, Robin M., additional, Higaki, Jeffrey N., additional, Liu, Yue, additional, Nijjar, Tarlochan, additional, Skov, Michael, additional, Zago, Wagner, additional, Yednock, Ted A., additional, Kinney, Gene F., additional, and Ness, Dan, additional

Published
2016
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45. Abstract 355: A monoclonal antibody against laminin alpha 4 inhibits both MCAM and integrin-a6b1 binding, blocks tumor cell adhesion in vitro and slows melanoma tumor growth in vivo

Author

Tam, Stephen J., primary, Li, Lauri E., additional, Lorenzana, Carlos, additional, Liu, Yue, additional, Flanagan, Ken, additional, Dolan, Philip J., additional, Alexander, Lana, additional, Salmans, Josh, additional, Barbour, Robin M., additional, Higaki, Jeffrey N., additional, Nijjar, Tarlochan, additional, Zago, Wagner, additional, Yednock, Ted A., additional, and Kinney, Gene, additional

Published
2015
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46. Abstract 1681: Inhibition of tumor growth in vivo through neutralization of the interaction of MCAM with laminin alpha 4

Author

Flanagan, Ken, primary, Li, Lauri W., additional, Lorenzana, Carlos, additional, Tam, Stephen J., additional, Liu, Yue, additional, Dolan, Philip J., additional, Alexander, Lana, additional, Salmans, Josh, additional, Barbour, Robin M., additional, Higaki, Jeffrey N., additional, Nijjar, Tarlochan, additional, Zago, Wagner, additional, Yednock, Ted A., additional, and Kinney, Gene, additional

Published
2015
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47. Characterization of Takusan, a Novel Gene Family that Regulates Synaptic Activity

Author

Tu, Shichun, Shin, Yeonsook, Zago, Wagner M., States, Bradley A., Eroshkin, Alexey, Lipton, Stuart A., Tong, Gary G., and Nakanishi, Nobuki

Subjects
Patch-Clamp Techniques, Green Fluorescent Proteins, Molecular Sequence Data, Transfection, Hippocampus, Receptors, N-Methyl-D-Aspartate, Article, Mice, Chlorocebus aethiops, Animals, Amino Acid Sequence, RNA, Messenger, Receptors, AMPA, RNA, Small Interfering, Cells, Cultured, Brain Chemistry, Mice, Knockout, Neurons, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Dendrites, Up-Regulation, Electrophysiology, nervous system, Multigene Family, COS Cells, Synapses, Disks Large Homolog 4 Protein, Guanylate Kinases
Abstract

We have characterized a rodent-specific gene family designated alpha-takusan (meaning "many" in Japanese). We initially identified a member of the family whose expression is upregulated in mice lacking the NMDAR subunit NR3A. We then isolated cDNAs encoding 46 alpha-takusan variants from mouse brains. Most variants share an approximately 130 aa long sequence, which contains the previously identified domain of unknown function 622 (DUF622) and is predicted to form coiled-coil structures. Single-cell PCR analyses indicate that one neuron can express multiple alpha-takusan variants and particular variants may predominate in certain cell types. Forced expression in cultured hippocampal neurons of two variants, alpha1 or alpha2, which bind either directly or indirectly to PSD-95, leads to an increase in PSD-95 clustering, dendritic spine density, GluR1 surface expression, and AMPAR activity. Conversely, treating cultured neurons with RNAi targeting alpha-takusan variants resulted in the opposite phenotype. Hence, alpha-takusan represents a large gene family that regulates synaptic activity.

Published
2007

48. A Novel Thiol Oxygen Sensor: Hypoxia Enhances S-Nitrosylation—Mediated Inhibition of NMDA Receptor Activity

Author

Takahashi, Hiroto, Shin, Yeonsook, Cho, Seung-Je, Zago, Wagner M., Nakamura, Tomohiro, Gu, Zezong, Ma, Yuliang, Furukawa, Hiroyasu, Liddington, Robert, Zhang, Dongxian, Tong, Gary, Chen, Huei-Sheng Vincent, and Lipton, Stuart A.

Subjects
Cerebral Cortex, Neurons, Binding Sites, S-Nitrosothiols, Amino Acid Motifs, Down-Regulation, Crystallography, X-Ray, Nitric Oxide, Receptors, N-Methyl-D-Aspartate, Article, Cell Line, Rats, Oxygen, Xenopus laevis, nervous system, Oocytes, Animals, Humans, Female, Disulfides, Sulfhydryl Compounds, Hypoxia, Brain, Reactive Oxygen Species, Oxidation-Reduction
Abstract

Under ambient air conditions, NO inhibits NMDA-sensitive glutamate receptor responses by reacting with C399 of the NR2A subunit as well as possibly with two pairs of cysteine residues if their disulfide bonds are reduced to free thiol (C744, C798 in NR1 and C87, C320 in NR2). Here we demonstrate that relative hypoxia enhances S-nitrosylation of NMDA receptors by a unique mechanism involving NR1(C744,C798), which constitutes a novel ‘NO-reactive oxygen sensor motif.’ These two critical thiol groups sensitize other sites on the NMDA receptor to S-nitrosylation and consequent inhibition of receptor activity, while manifesting little if any effect on NMDA receptor activity by their own nitrosylation. The crystal structure of NR1 reveals a uniquely flexible (C744-C798) disulfide bond, which may account for the susceptibility of these two cysteines to reduction and subsequent facile oxidation by NO, as observed with biochemical techniques. Our findings have important implications for the treatment of hypoxia/stroke because these thiol groups can be nitrosylated preferentially during relative hypoxia, thus abrogating excessive activity associated with cytotoxicity while avoiding side effects caused by blockade of normal NMDA receptors.

Published
2007

50. Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson’s Disease

Author

Tóth, Gergely, primary, Gardai, Shyra J., additional, Zago, Wagner, additional, Bertoncini, Carlos W., additional, Cremades, Nunilo, additional, Roy, Susan L., additional, Tambe, Mitali A., additional, Rochet, Jean-Christophe, additional, Galvagnion, Celine, additional, Skibinski, Gaia, additional, Finkbeiner, Steven, additional, Bova, Michael, additional, Regnstrom, Karin, additional, Chiou, San-San, additional, Johnston, Jennifer, additional, Callaway, Kari, additional, Anderson, John P., additional, Jobling, Michael F., additional, Buell, Alexander K., additional, Yednock, Ted A., additional, Knowles, Tuomas P. J., additional, Vendruscolo, Michele, additional, Christodoulou, John, additional, Dobson, Christopher M., additional, Schenk, Dale, additional, and McConlogue, Lisa, additional

Published
2014
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