Initiation and propagation of alpha synuclein oligomers--Relevance for Parkinson s disease
Final Report Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the accumulation of alpha-synuclein (α-syn) protein aggregates, leading to neuronal dysfunction and progressive motor impairment. The Emmy Noether Program aimed to investigate the mechanisms of α-syn propagation focusing on three key hypotheses. The first hypothesis explored how specific α-syn oligomers spread between neurons and other cell types, potentially driving neurodegeneration. Using advanced transgenic mouse models, we demonstrate the presence of α-syn oligomers in different brain regions and their transmission between neurons. Age-dependent accumulation of these oligomers correlated with motor deficits and dopaminergic neuron loss. The second hypothesis investigated the interaction between α-syn and immune cells, particularly monocytes and microglia. We found that α-syn oligomers, especially those associated with extracellular vesicles (EVs), strongly activated monocytes and induced inflammatory responses. These findings support the idea that immune dysregulation contributes to PD pathology, as PD patient-derived EVs triggered stronger immune reactions than those from healthy individuals. The third hypothesis examined the role of EV microRNAs in PD-related neurodegeneration. Although we identified several dysregulated miRNAs in PD serum, their diagnostic value was limited. Consequently, the study pivoted to analyzing mitochondrial DNA and blood cell transcriptomes in amyotrophic lateral sclerosis (ALS) patients, yielding valuable insights into neurodegenerative disease mechanisms. Overall, this research significantly advances our understanding of PD pathogenesis by elucidating α-syn transmission, immune activation, and molecular biomarkers.
Publications
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Age Increases Monocyte Adhesion on Collagen. Scientific Reports, 7(1).
Khalaji, Samira; Zondler, Lisa; KleinJan, Fenneke; Nolte, Ulla; Mulaw, Medhanie A.; Danzer, Karin M.; Weishaupt, Jochen H. & Gottschalk, Kay-E.
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Proteasome impairment by α-synuclein. PLOS ONE, 12(9), e0184040.
Zondler, Lisa; Kostka, Marcus; Garidel, Patrick; Heinzelmann, Udo; Hengerer, Bastian; Mayer, Benjamin; Weishaupt, Jochen H.; Gillardon, Frank & Danzer, Karin M.
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The Golgi-localized, gamma ear-containing, ARF-binding (GGA) protein family alters alpha synuclein (α-syn) oligomerization and secretion. Aging, 9(7), 1677-1697.
von Einem, Bjoern; Eschbach, Judith; Kiechle, Martin; Wahler, Anke; Thal, Dietmar R.; McLean, Pamela J.; Weishaupt, Jochen H.; Ludolph, Albert C.; von Arnim, Christine A.F. & Danzer, Karin M.
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Release and uptake of pathologic alpha-synuclein. Cell and Tissue Research, 373(1), 175-182.
Grozdanov, Veselin & Danzer, Karin M.
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Increased Immune Activation by Pathologic α‐Synuclein in Parkinson's Disease. Annals of Neurology, 86(4), 593-606.
Grozdanov, Veselin; Bousset, Luc; Hoffmeister, Meike; Bliederhaeuser, Corinna; Meier, Christoph; Madiona, Karine; Pieri, Laura; Kiechle, Martin; McLean, Pamela J.; Kassubek, Jan; Behrends, Christian; Ludolph, Albert C.; Weishaupt, Jochen H.; Melki, Ronald & Danzer, Karin M.
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In Vivo Protein Complementation Demonstrates Presynaptic α-Synuclein Oligomerization and Age-Dependent Accumulation of 8–16-mer Oligomer Species. Cell Reports, 29(9), 2862-2874.e9.
Kiechle, Martin; von Einem, Bjoern; Höfs, Lennart; Voehringer, Patrizia; Grozdanov, Veselin; Markx, Daniel; Parlato, Rosanna; Wiesner, Diana; Mayer, Benjamin; Sakk, Olena; Baumann, Bernd; Lukassen, Soeren; Liss, Birgit; Ekici, Arif B.; Ludolph, Albert C.; Walther, Paul; Ferger, Boris; McLean, Pamela J.; Falkenburger, Björn H. ... & Danzer, Karin M.
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Enhanced Hyaluronan Signaling and Autophagy Dysfunction by VPS35 D620N. Neuroscience, 441, 33-45.
Rahman, Abir A.; Soto-Avellaneda, Alejandro; Yong Jin, Hyun; Stojkovska, Iva; Lai, Nathan K.; Albright, Joshua E.; Webb, Abby R.; Oe, Emily; Valarde, Jacob P.; Oxford, Alexandra E.; Urquhart, Paige E.; Wagner, Brandon; Brown, Connor; Amado, Isabella; Vasquez, Peyton; Lehning, Nicholas; Grozdanov, Veselin; Pu, Xinzhu; Danzer, Karin M. & Morrison, Brad E.
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Intracellular Alpha-Synuclein and Immune Cell Function. Frontiers in Cell and Developmental Biology, 8.
Grozdanov, Veselin & Danzer, Karin M.
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The Role of Lipids in the Initiation of α-Synuclein Misfolding. Frontiers in Cell and Developmental Biology, 8.
Kiechle, Martin; Grozdanov, Veselin & Danzer, Karin M.
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Protein Binding Partners of Dysregulated miRNAs in Parkinson’s Disease Serum. Cells, 10(4), 791.
Ruf, Wolfgang P.; Freischmidt, Axel; Grozdanov, Veselin; Roth, Valerie; Brockmann, Sarah J.; Mollenhauer, Brit; Martin, Dorothea; Haslinger, Bernhard; Fundel-Clemens, Katrin; Otto, Markus; Arnim, Christine von; Holzmann, Karlheinz; Ludolph, Albert C.; Weishaupt, Jochen H. & Danzer, Karin M.
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T-cell dysregulation is associated with disease severity in Parkinson’s Disease. Journal of Neuroinflammation, 18(1).
Bhatia, Divisha; Grozdanov, Veselin; Ruf, Wolfgang P.; Kassubek, Jan; Ludolph, Albert C.; Weishaupt, Jochen H. & Danzer, Karin M.
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Increased NF-L levels in the TDP-43G298S ALS mouse model resemble NF-L levels in ALS patients. Acta Neuropathologica, 144(1), 161-164.
Buck, Eva; Oeckl, Patrick; Grozdanov, Veselin; Bopp, Verena; Kühlwein, Julia K.; Ruf, Wolfgang P.; Wiesner, Diana; Roselli, Francesco; Weishaupt, Jochen H.; Ludolph, Albert C.; Otto, Markus & Danzer, Karin M.
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Stress induced TDP-43 mobility loss independent of stress granules. Nature Communications, 13(1).
Streit, Lisa; Kuhn, Timo; Vomhof, Thomas; Bopp, Verena; Ludolph, Albert C.; Weishaupt, Jochen H.; Gebhardt, J. Christof M.; Michaelis, Jens & Danzer, Karin M.
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Thoracic trauma promotes alpha-Synuclein oligomerization in murine Parkinson's disease. Neurobiology of Disease, 174, 105877.
Ruf, Wolfgang P.; Palmer, Annette; Dörfer, Lena; Wiesner, Diana; Buck, Eva; Grozdanov, Veselin; Kassubek, Jan; Dimou, Leda; Ludolph, Albert C.; Huber-Lang, Markus & Danzer, Karin M.
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ALS is imprinted in the chromatin accessibility of blood cells. Cellular and Molecular Life Sciences, 80(5).
Kühlwein, Julia K.; Ruf, Wolfgang P.; Kandler, Katharina; Witzel, Simon; Lang, Christina; Mulaw, Medhanie A.; Ekici, Arif B.; Weishaupt, Jochen H.; Ludolph, Albert C.; Grozdanov, Veselin & Danzer, Karin M.
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DNA Methylation Analysis in Monozygotic Twins Discordant for ALS in Blood Cells. Epigenetics Insights, 16.
Yazar, Volkan; Ruf, Wolfgang P.; Knehr, Antje; Günther, Kornelia; Ammerpohl, Ole; Danzer, Karin M. & Ludolph, Albert C.
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Impaired ATF3 signaling involves SNAP25 in SOD1 mutant ALS patients. Scientific Reports, 13(1).
Yazar, Volkan; Kühlwein, Julia K.; Knehr, Antje; Grozdanov, Veselin; Ekici, Arif B.; Ludolph, Albert C. & Danzer, Karin M.
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Low T-cell reactivity to TDP-43 peptides in ALS. Frontiers in Immunology, 14.
Ramachandran, Swetha; Grozdanov, Veselin; Leins, Bianca; Kandler, Katharina; Witzel, Simon; Mulaw, Medhanie; Ludolph, Albert C.; Weishaupt, Jochen H. & Danzer, Karin M.
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Mitochondrial genome study in blood of maternally inherited ALS cases. Human Genomics, 17(1).
Brockmann, Sarah J.; Buck, Eva; Casoli, Tiziana; Meirelles, João L.; Ruf, Wolfgang P.; Fabbietti, Paolo; Holzmann, Karlheinz; Weishaupt, Jochen H.; Ludolph, Albert C.; Conti, Fiorenzo & Danzer, Karin M.
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Spreading of alpha-synuclein between different cell types. Behavioural Brain Research, 436, 114059.
Ruf, Wolfgang P.; Meirelles, Joao L. & Danzer, Karin M.
