Pathological mechanisms of synaptic vesicle recycling

• Antragstellerin: Dr. Ira Milosevic
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2012 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 224837277

The molecular basis of cellular pathology for the majority of neurodegenerative diseases is not well understood. As research progresses, some similarities that relate different neurodegenerative disorders emerge at the molecular level. Discovering and understanding such resemblances offers hope for therapeutic advances that could ameliorate several neurodegenerative diseases. I have recently characterized animals with impaired function of the endocytic adaptor endophilin that, in addition to defective synaptic vesicle recycling, show neurodegeneration and prominent neurological defects, including ataxia and epilepsy (Milosevic et al, 2011; PMID:22099461). I hypothesize that these endophilin-associated defects are physically and functionally linked, and aim to explore the mechanistic basis for this. My objectives include unraveling the role of synaptic vesicle recycling in neurodegeneration, with the emphasis on the identification of signaling pathways that mediate neurodegeneration originating form endocytic defects and the relevance of the high-affinity Parkin-endophilin A interaction to Parkinson´s disease, and identification of molecular mechanisms of SV re-formation and maturation, with a focus on a role of endophilin. Further, I am committed to develop novel therapeutics for some debilitating disorders such as Parkinson´s disease and epilepsy, and will thus search for small molecules that specifically regulate uncoating of clathrin coated vesicles. Overall, these objectives will also provide new insights in neurotransmission. Given a central role of synaptic transmission for nervous system function, these topics are essential for neurobiology and relevant for the understanding and potential treatment several neurodegenerative and neurological diseases. Hence, these proposed studies will have wide implications for cell biology, physiology and medicine.

• DFG-Verfahren: Emmy Noether-Nachwuchsgruppen
• Großgeräte: inverted microscope with electrophysiological setup
• Gerätegruppe: 5040 Spezielle Mikroskope (außer 500-503)