synaptic proteostasis and neurodegenerative disease
High-rate neuronal firing damages essential synaptic vesicle proteins, creating a need for rapid turnover. When this turnover is compromised, aggregates can form. Most of the time these protein aggregates cannot be efficiently cleared from synapses, leading to synaptic dysfunction. Synaptic dysfunction is an early hallmark of many neurological disorders, including Parkinson’s disease. To maintain a healthy proteome, synapses must sort functional from damaged proteins. Currently it is unknown how or where this sorting is accomplished and how protein aggregates are removed from synapses. To elucidate this sorting mechanism, we are tracking vesicle proteins using zap-and-freeze electron microscopy and other techniques. We are also investigating if sorting is implicated in Parkinson’s disease, by characterizing the potential role of leucine-rich repeat kinase 2 (LRRK2) in vesicle protein sorting. Overall we are resolving synaptic proteostasis mechanisms in health and disease using innovative transmission electron microscopy based methods.
current projects:
- Determining the mechanism of vesicle protein sorting in ultrafast endocytosis
- Investigating how damaged proteins are sorted out of the synaptic vesicle cycle
- Examining the role of LRRK2 in synaptic protein sorting
- Characterizing how newly synthesized proteins are integrated into the synaptic vesicle cycle
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