SYNPT · The role of autophagy in presynaptic protein turnover
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-05-01 → 2017-04-30
- EU contribution
- €159,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
The role of autophagy in presynaptic protein turnover
During the course of cellular life, macromolecules, proteins and organelles become damaged or otherwise unwanted. Proper disposal of these unwanted cellular components is essential for cell functioning. While most cells are capable of diluting out cellular waste by division, non-dividing neurons are extremely prone to accumulate damaged components over time. Therefore, proper waste management is extremely important for healthy neuron functioning. One of the systems responsible for the removal of proteins and organelles is autophagy. During autophagy a defined set of proteins (Atg, or autophagy-related proteins) coordinate the orderly degradation and recycling of cellular components. A membrane compartment termed the isolation-membrane is formed, expands in size and eventually closes to form a double-membrane vesicle called the autophagosome. Finally, the resulting autophagosome fuses with the lysosome where its cargo is degraded. This pathway has been implicated in many cellular processes such as neuronal development and ageing. Dysfunctional autophagy has been shown to contribute to neurodegeneration and is linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, the two neurodegenerative disorders of highest prevalence in our society. Moreover, autophagic activity declines during aging and enhancing expression of autophagy genes has been proven effective in prolonging life span. Consequently, understanding the mechanisms underlying autophagic degradation and finding the substrates targeted by this pathway will provide essential knowledge to fight age-related disorders and improve health span in our aging population. Interneuronal communication primarily takes place at synapses. Over the years studies have shown that protein synthesis and degradation processes affect the properties of synapses by changing the abundance of particular synaptic proteins in a spatially confined manner. Studying protein turnover and autophagy in the presynapse will help to understand how plastic changes occur at the level of individual synapses and give insights into the role of autophagy in neurodegenerative diseases. To this end I characterized the role of autophagy in presynaptic protein degradation and synaptic functioning. Unexpectedly, the degradation of most proteins, including presynaptic proteins, was not affected upon autophagy inhibition.
Data: CORDIS, © European Union
Project objective
Neuronal communication primarily occurs at synapses. Recent studies have suggested a key role for protein synthesis and degradation in the regulation of synaptic structure, function and plasticity by changing the abundance of select synaptic proteins in a spatially confined manner. Remodeling of the synaptic proteome is accomplished by, for example, regulated degradation via the ubiquitin proteasome system or by autophagy. Autophagy has been shown to modulate synaptic vesicle numbers and neurotransmission, yet its exact role in the regulation of synaptic function is poorly understood. The proposed project aims at the dissection of the role of autophagy in synaptic protein turnover. Using combined genetic, biochemical, molecular and cellular biology approaches as well as cutting-edge imaging in neurons I will identify presynaptic proteins that are regulated by autophagy and will define the contribution of autophagy to synapse composition and function. Furthermore, I will determine which mechanisms underlie the selective targeting of presynaptic proteins to the autophagy pathway. Taken together these studies will contribute fundamental knowledge about autophagy in neurons and will provide new insights for understanding how autophagy contributes to synaptic plasticity and protein degradation in health and disease.
Original text from CORDIS.
Participants
- FORSCHUNGSVERBUND BERLIN EV · BerlinCoordinatorGermany
Links
Data: CORDIS, © European Union