Mechanism of alpha-synuclein aggregate clearance by Rab7
Final Report Abstract
Parkinson's disease is characterized by aggregates of misfolded proteins, in particular alphasynuclein. Our aim is to stop progression of Parkinson's disease by inducing clearance of alpha-synuclein aggregates. Aggregates are degraded by autophagy where pieces of cytosol are engulfed by a membrane. These autophagosomes subsequently fuse with lysosomes to degrade their content. In previous work we could show that autolysosomal degradation of alpha-synuclein aggregates is induced by overexpression of Rab7. Several Rab proteins promote aggregate clearance, but Rab7 is of particular interest since it mediates effects of PINK, parkin and LRRK2; mutations in the genes that encode these proteins are associated with familial Parkinson's disease. In the proposed study, we investigated which molecules mediate Rab7-induced aggregate clearance and which cellular events underlie this effect. Our goal was to better understand aggregate clearance and to develop new therapeutic strategies. An important result was that the protective effect of Rab7 could be confirmed with studies on the brains of mice. Stabilization of individual synuclein molecules was also able to reduce the formation of synuclein aggregates in mice. In a project based on the methods established in this project, we were also able to show that chronic inflammation in the brain is sufficient to form synuclein aggregates. This finding may explain why neurodegenerative diseases often begin after systemic infections. In addition, we have established improved cellular models of Parkinson's disease. These use neurons derived from human stem cells, which may better represent the pathology in humans than animal cells. In another model, we use aggregates from biosamples to reproduce the exact pathology of individual patients in our cellular models. The vesicles involved in the degradation of synuclein aggregates are transported in the cell along microtubules. These transport processes allow different steps of synuclein degradation to take place at specialized locations in the cell; the fusion of autophagosomes with lysosomes, for example, takes place in the center of the cell. During maturation, the content of autolysosomes is increasingly acidified; this process is associated with transport to the surface of the cell. Substances that open ion channels on these vesicles can improve the formation of autolysosomes from autophagosomes and lysosomes; this also improves the degradation of synuclein aggregates and may be used therapeutically in the future.
Publications
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Cholesterol transfer at ER-endosome contact sites and α-synuclein clearance. Dissertation (Dr. med.), RWTH Aachen.
Gorzel, K. M.
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Degradation of α-synuclein aggregates through aggresome formation, autophagy and Rab7. Dissertation (Dr.med.), RWTH Aachen.
Diederichs, L.
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Parkinson’s disease and translational research. Translational Neurodegeneration, 9(1).
Dinter, Elisabeth; Saridaki, Theodora; Diederichs, Leonie; Reichmann, Heinz & Falkenburger, Björn H.
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A β-Wrapin Targeting the N-Terminus of α-Synuclein Monomers Reduces Fibril-Induced Aggregation in Neurons. Frontiers in Neuroscience, 15.
Szegő, Éva M.; Boß, Fabian; Komnig, Daniel; Gärtner, Charlott; Höfs, Lennart; Shaykhalishahi, Hamed; Wördehoff, Michael M.; Saridaki, Theodora; Schulz, Jörg B.; Hoyer, Wolfgang & Falkenburger, Björn H.
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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1. Autophagy, 17(1), 1-382.
Klionsky, Daniel J.; Abdel-Aziz, Amal Kamal; Abdelfatah, Sara; Abdellatif, Mahmoud; Abdoli, Asghar; Abel, Steffen; Abeliovich, Hagai; Abildgaard, Marie H.; Abudu, Yakubu Princely; Acevedo-Arozena, Abraham; Adamopoulos, Iannis E.; Adeli, Khosrow; Adolph, Timon E.; Adornetto, Annagrazia; Aflaki, Elma; Agam, Galila; Agarwal, Anupam; Aggarwal, Bharat B.; Agnello, Maria ... & Tong, Chun-Kit
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Maturing Autophagosomes are Transported Towards the Cell Periphery. Cellular and Molecular Neurobiology, 42(1), 155-171.
Hilverling, Anna; Szegö, Eva M.; Dinter, Elisabeth; Cozma, Diana; Saridaki, Theodora & Falkenburger, Björn H.
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Activated Endolysosomal Cation Channel TRPML1 Facilitates Maturation of α-Synuclein-Containing Autophagosomes. Frontiers in Cellular Neuroscience, 16.
Pollmanns, Maike R.; Beer, Judith; Rosignol, Ines; Rodriguez-Muela, Natalia; Falkenburger, Björn H. & Dinter, Elisabeth
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Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice. eLife, 11.
Szego, Eva M.; Malz, Laura; Bernhardt, Nadine; Rösen-Wolff, Angela; Falkenburger, Björn H. & Luksch, Hella
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Der Effekt von FYCO1 auf Autophagosomen und Synuklein-Abbau in primären Maus-Neuronen. Dissertation (Dr. med.), RWTH Aachen.
Grafe, C.
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Examination of chemically activated lysosomal ion channel in a cellular model of Parkinson’s Disease. Dissertation (Dr. med.), RWTH Aachen.
Pollmanns, Maike
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Rab7 reduces α-synuclein toxicity in rats and primary neurons. Experimental Neurology, 347, 113900.
Szegö, Eva M.; Van den Haute, Chris; Höfs, Lennart; Baekelandt, Veerle; Van der Perren, Anke & Falkenburger, Björn H.
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The effect of Rab9 and RabEPK on alpha-synuclein aggregates. Dissertation (Dr. med.), RWTH Aachen.
Albuscheit, N.
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The effects of Rab7 overexpression on synuclein pathology in a rodent model of Parkinson’s disease. Dissertation (Dr. med.), RWTH Aachen.
Höfs, L.
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Examining FYCO1 as a modulator of autophagy for a-synuclein aggregate clearance in hiPSC derived neurons. Dissertation (PhD), Technische Universität Dresden.
Beer, J.
