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Decipher how mRNAs are captured at specific subcellular locations to support local translation in neurons

Project description

Mechanisms for the local capture and selective translation of mRNAs

Brain function requires careful regulation of the neuronal proteome, which involves localising mRNAs to neurites where translation occurs at precise subcellular locations. Dysregulation of mRNA localisation and translation can lead to neurological disorders such as amyotrophic lateral sclerosis (ALS). However, the mechanisms for the capture and translation of specific mRNAs at precise locations are unclear. The ERC-funded RNA.ORG project aims to identify how the coordination between mRNA transport, capture and local translation occurs. Based on recent findings that organelles coordinate mRNA distribution, local capture and selective translation, RNA.ORG has developed novel tools to visualise and adjust organelle position and contacts at nanoscale resolution. Using these tools, it will manipulate mRNA positioning to prevent its dysregulation in ALS.

Objective

Brain function requires precise regulation of the neuronal proteome which involves localizing thousands of mRNAs to neurites, where specific subsets are translated at the required subcellular locations. Although local translation is well-established, the mechanisms that ensure the capture and translation of specific mRNAs at the correct subcellular location remain elusive. A better understanding of this process is urgent since dysregulation of mRNA localization and translation is emerging as a key pathological event in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).

In RNA.ORG I aim to define, at a molecular level, how the coordination between mRNA transport, capture and local translation occurs to support neuronal function.
Recent work from my lab and others has shown that multiple organelles interact with mRNA and translational machinery. This raises the exciting possibility that organelle interactions coordinate mRNA distribution, local capture and selective translation. I have developed tools to visualize and manipulate organelle position and contacts at nanoscale resolution. Here, I will leverage these tools and directly control mRNA positioning to elucidate the importance of mRNA capture in neuronal function and intervene in its dysregulation in ALS.
In combination with live-cell and super-resolution imaging, RNA-sequencing and proteomics, this project will address the following key objectives:
1) Resolve the subcellular distribution and dynamics of neuronal organelle-mRNA contacts
2) Unravel the functions of organelle-mediated mRNA capture at specific subcellular locations
3) Determine the role of dysregulated mRNA capture in amyotrophic lateral sclerosis

RNA.ORG will elucidate novel mechanisms on the subcellular capture and translation of specific mRNAs in neurons and will provide new insights into the role of local mRNA positioning in neuronal development, physiology and pathology.

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2024-STG

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Host institution

STICHTING VU
Net EU contribution

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€ 1 499 140,00
Address
DE BOELELAAN 1105
1081 HV Amsterdam
Netherlands

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Activity type
Higher or Secondary Education Establishments
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Total cost

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€ 1 499 140,00

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