Urmi Sengupta1, Marcos J Guerrero-Muñoz1, Diana L Castillo-Carranza1, Cristian A Lasagna-Reeves1, Julia E Gerson1, Adriana A Paulucci-Holthauzen2, Shashirekha Krishnamurthy1, Malika Farhed1, George R Jackson3, Rakez Kayed4. 1. Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas; Departments of Neurology and Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas. 2. Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas. 3. Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas; Departments of Neurology and Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas; Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas. 4. Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, Texas; Departments of Neurology and Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas; Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas. Electronic address: rakayed@utmb.edu.
Abstract
BACKGROUND: Aberrant accumulation of α-synuclein constitutes inclusion bodies that are considered a characteristic feature of a group of neurological disorders described as synucleinopathies. Often, multiple disease-causing proteins overlap within a given disease pathology. An emerging body of research focuses on the oligomeric populations of various pathogenic proteins, considering them as the culprits causing neuronal damage and degeneration. To this end, the use of conformation-specific antibodies has proven to be an effective tool. Previous work from our laboratory and others has shown that oligomeric entities of α-synuclein and tau accumulate in their respective diseases, but their interrelationship at this higher order has yet to be shown in synucleinopathies. METHODS: Here, we used two novel conformation-specific antibodies, F8H7 and Syn33, which recognize α-synuclein oligomers and were developed in our laboratory. We investigated brain tissue from five of each Parkinson's disease and dementia with Lewy bodies patients by performing biophysical and biochemical assays using these antibodies, in addition to the previously characterized anti-tau oligomer antibody T22. RESULTS: We demonstrate that in addition to the deposition of oligomeric α-synuclein, tau oligomers accumulate in these diseased brains compared with control brains. Moreover, we observed that oligomers of tau and α-synuclein exist in the same aggregates, forming hybrid oligomers in these patients' brains. CONCLUSIONS: In addition to the deposition of tau oligomers, our results also provide compelling evidence of co-occurrence of α-synuclein and tau into their most toxic forms, i.e., oligomers suggesting that these species interact and influence each other's aggregation via an interface in synucleinopathies.
BACKGROUND: Aberrant accumulation of α-synuclein constitutes inclusion bodies that are considered a characteristic feature of a group of neurological disorders described as synucleinopathies. Often, multiple disease-causing proteins overlap within a given disease pathology. An emerging body of research focuses on the oligomeric populations of various pathogenic proteins, considering them as the culprits causing neuronal damage and degeneration. To this end, the use of conformation-specific antibodies has proven to be an effective tool. Previous work from our laboratory and others has shown that oligomeric entities of α-synuclein and tau accumulate in their respective diseases, but their interrelationship at this higher order has yet to be shown in synucleinopathies. METHODS: Here, we used two novel conformation-specific antibodies, F8H7 and Syn33, which recognize α-synuclein oligomers and were developed in our laboratory. We investigated brain tissue from five of each Parkinson's disease and dementia with Lewy bodiespatients by performing biophysical and biochemical assays using these antibodies, in addition to the previously characterized anti-tau oligomer antibody T22. RESULTS: We demonstrate that in addition to the deposition of oligomeric α-synuclein, tau oligomers accumulate in these diseased brains compared with control brains. Moreover, we observed that oligomers of tau and α-synuclein exist in the same aggregates, forming hybrid oligomers in these patients' brains. CONCLUSIONS: In addition to the deposition of tau oligomers, our results also provide compelling evidence of co-occurrence of α-synuclein and tau into their most toxic forms, i.e., oligomers suggesting that these species interact and influence each other's aggregation via an interface in synucleinopathies.
Authors: Julia Gerson; Diana L Castillo-Carranza; Urmi Sengupta; Riddhi Bodani; Donald S Prough; Douglas S DeWitt; Bridget E Hawkins; Rakez Kayed Journal: J Neurotrauma Date: 2016-04-22 Impact factor: 5.269
Authors: Megan E Larson; Susan J Greimel; Fatou Amar; Michael LaCroix; Gabriel Boyle; Mathew A Sherman; Hallie Schley; Camille Miel; Julie A Schneider; Rakez Kayed; Fabio Benfenati; Michael K Lee; David A Bennett; Sylvain E Lesné Journal: Proc Natl Acad Sci U S A Date: 2017-05-22 Impact factor: 11.205
Authors: Elyse Rosa; Sujeivan Mahendram; Yazi D Ke; Lars M Ittner; Stephen D Ginsberg; Margaret Fahnestock Journal: Neurobiol Aging Date: 2016-08-31 Impact factor: 4.673