Autophagy modulates alpha-Synuclein cellular pathology and exosome associated release

• Applicant: Professor Dr. Jochen Klucken
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317761452

• Final Report Year: 2023

Final Report Abstract

Synucleinopathies like Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) feature inclusions (Lewy bodies, LBs, and Lewy neurites, LNs) containing misfolded alpha‐synuclein. The autophagy‐lysosomal pathway (ALP) and the ubiquitin‐proteasome degradation system (UPS) contribute to alpha‐synuclein degradation. In the DFG supported project we have examined the role of alpha‐synuclein aggregation, toxicity and linked it to autophagosomal degradation and its exosome‐mediated secretion. We could identify a novel autophagosome‐related secretion mechanism of alpha‐synuclein – termed autophagoexosome – that was responsible for the transmission of potentially toxic or pro‐aggregation prone forms of alpha‐synuclein. This could be validated in the blood, the CSF of patients, as well as mechanistically in the brain of injected mice. This completely new mechanisms made it to the front‐page of the corresponding Volume of the prestigious Journal Autophagy in 2018. In addition, we explored the responsiveness of the autophagy‐alpha‐synuclein interaction to a physical intervention in a rodent model of alpha‐synuclein aggregation. Here, we could show that physical exercise – e.g. treadmill intervention – could have a protective role on alpha‐synucleinopathies. This was published in the Journal of Behavioral Brain Research in 2019 and complemented the applicants other focus where he tested treadmill intervention in Parkinson Patients. The combination of molecular‐mechanistic assessments of alpha‐synuclein pathology and autophagic processing with physical exercise intervention also led to the integration of a new phenotypical assessment of gait in mice (Cat‐Walk‐Test) which revealed to be a very sensitive readout for interventional effects in alpha‐ synuclein mice. This medical‐technical project arm was innovatively added during the funding period and thus, complementing the anticipated phenotypical assessment methodologies proposed in the DFG project application. The results were published in the Journal of Neuroscientific Methods.

Publications

• Alpha‐synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress Sci Rep, 7: 42942
  Menges, Minakaki, Schaefer, Meixner, Prots, Schlotzer‐Schrehardt, Friedland, Winner, Outeiro, Winklhofer, von Arnim, Xiang, Winkler & Klucken
  
• Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. Brain, 140(5), 1399-1419.
  Vicente Miranda, Hugo; Szegő, Éva M.; Oliveira, Luís M. A.; Breda, Carlo; Darendelioglu, Ekrem; de Oliveira, Rita M.; Ferreira, Diana G.; Gomes, Marcos A.; Rott, Ruth; Oliveira, Márcia; Munari, Francesca; Enguita, Francisco J.; Simões, Tânia; Rodrigues, Eva F.; Heinrich, Michael; Martins, Ivo C.; Zamolo, Irina; Riess, Olaf; Cordeiro, Carlos; ... & Outeiro, Tiago F.
  
• Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy, 14(1), 98-119.
  Minakaki, Georgia; Menges, Stefanie; Kittel, Agnes; Emmanouilidou, Evangelia; Schaeffner, Iris; Barkovits, Katalin; Bergmann, Anna; Rockenstein, Edward; Adame, Anthony; Marxreiter, Franz; Mollenhauer, Brit; Galasko, Douglas; Buzás, Edit Irén; Schlötzer-Schrehardt, Ursula; Marcus, Katrin; Xiang, Wei; Lie, Dieter Chichung; Vekrellis, Kostas; Masliah, Eliezer; ... & Klucken, Jochen
  
• FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis. Neuron, 99(6), 1188-1203.e6.
  Schäffner, Iris; Minakaki, Georgia; Khan, M. Amir; Balta, Elli-Anna; Schlötzer-Schrehardt, Ursula; Schwarz, Tobias J.; Beckervordersandforth, Ruth; Winner, Beate; Webb, Ashley E.; DePinho, Ronald A.; Paik, Jihye; Wurst, Wolfgang; Klucken, Jochen & Lie, D. Chichung
  
• Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose. Scientific Reports, 9(1).
  Hoffmann, Anna-Carin; Minakaki, Georgia; Menges, Stefanie; Salvi, Rachele; Savitskiy, Sergey; Kazman, Aida; Vicente, Miranda Hugo; Mielenz, Dirk; Klucken, Jochen; Winkler, Jürgen & Xiang, Wei
  
• Treadmill exercise intervention improves gait and postural control in alpha-synuclein mouse models without inducing cerebral autophagy. Behavioural Brain Research, 363, 199-215.
  Minakaki, Georgia; Canneva, Fabio; Chevessier, Frédéric; Bode, Frederik; Menges, Stefanie; Timotius, Ivanna K.; Kalinichenko, Liubov S.; Meixner, Holger; Müller, Christian P.; Eskofier, Bjoern M.; Casadei, Nicolas; Riess, Olaf; Schröder, Rolf; Winkler, Jürgen; Xiang, Wei; von Hörsten, Stephan & Klucken, Jochen
  
• Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) Autophagy, 17: 1‐382
  Klionsky, Abdel‐Aziz, Abdelfatah, Abdellatif & Klucken et al.
  
• Blood-based biomarker in Parkinson’s disease: potential for future applications in clinical research and practice. Journal of Neural Transmission, 129(9), 1201-1217.
  Tönges, Lars; Buhmann, Carsten; Klebe, Stephan; Klucken, Jochen; Kwon, Eun Hae; Müller, Thomas; Pedrosa, David J.; Schröter, Nils; Riederer, Peter & Lingor, Paul