Project description
Elucidating alternative protein sorting route in neurons
Newly synthesised transmembrane proteins reach the plasma membrane through the rough endoplasmic reticulum and Golgi apparatus. However, it is unclear whether protein sorting in neuronal axons follows the same route or whether it bypasses the Golgi. The EU-funded NEUROSORTER project aims to investigate the mechanisms responsible for the polarised distribution of proteins in neurons which is key for their function. Researchers will identify the sorting routes for newly synthesised axonal proteins using spatiotemporal resolution imaging and mass-spectrometry. Results will provide important knowledge on the existence of an alternative protein sorting route in neurons and help understand diseases associated with this pathway.
Objective
Neuronal development and function rely on the polarized distribution of organelles and transmembrane proteins (cargoes) across their somatodendritic and axonal domains. However, it is unknown how organelle organization regulates the polarized sorting of transmembrane proteins to ensure proper neuronal function.
The classical model for sorting of newly synthesized transmembrane proteins to the plasma membrane (PM) follows the biosynthetic pathway via the rough endoplasmic reticulum (ER) and Golgi, which are restricted to the somatodendritic domain in neurons. It is unclear whether this classical secretion pathway is the main route for cargo sorting into the axon or whether an alternative route to the axon is used for most axonal cargoes. Intriguingly, evidence indicates that cargoes can bypass the Golgi for their sorting to the axonal PM. However, the identity of an unconventional secretory pathway has not been demonstrated yet. Here, I propose that selective machinery, including the axonal ER and undefined intermediate compartments, allows local axonal cargo secretion.
Previously, I advanced our knowledge on Golgi-dependent sorting of somatodendritic cargoes and elucidated the mechanisms behind ER organization in neurons. Here, for the first time we will:
1) Identify the sorting routes for newly synthesized axonal proteins
2) Unravel the machinery required for Golgi-independent cargo sorting into the axon, and
3) Elucidate its impact on neuronal development and function
We will use high spatio-temporal resolution imaging and mass-spectrometry combined with novel strategies to control and track cargo secretion, as well as proximity-based labeling to identify key players in the newly identified machinery.
A broad spectrum of human diseases is associated to cargo Golgi-bypass. Neurons offer a unique advantage in spatial resolution to characterize this unconventional route, which could play a key role in human health and disease.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- natural sciences biological sciences biochemistry biomolecules proteins
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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3584 CS Utrecht
Netherlands
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