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Deciphering ubiquitin-dependent regulation of Golgi homeostasis control in neurodegeneration

Project description

Dissecting Golgi fragmentation in neurodegenerative disorders

The Golgi apparatus is an organelle in eukaryotic cells that processes and sorts proteins destined for the plasma membrane or for secretion. Therefore, it plays a key role in cellular homeostasis and cell-to-cell communication. The Golgi is a highly dynamic organelle that maintains a specific morphology but becomes irreversibly fragmented in neurodegenerative conditions such as Alzheimer’s disease. The scope of the EU-funded UbiGolD project is to investigate the mechanisms that regulate Golgi fragmentation. Researchers will focus on a novel proteasomal degradation mechanism and its role in Golgi integrity under changing conditions. Results will shed light on neurodegeneration and pave the way towards new treatments.

Objective

Alzheimer’s disease (AD) is the most common neurodegenerative disorder which affects 47 million patients worldwide. However, the underlying molecular mechanisms leading to sporadic-AD remain unknown and preventive treatment is not yet available. Lately, the ubiquitin-proteasome system has been implicated in AD. Dr. Merbl’s laboratory recently discovered a novel mechanism of Golgi-localized proteasomal degradation that controls Golgi integrity under stress. As the Golgi apparatus is the major hub required for protein secretion and plasma membrane localization, its proper function is crucial for maintaining cellular homeostasis and controlled cell-cell communication. This intriguing finding may be of instrumental importance to evidence of Golgi fragmentation which is observed in neurons in neurodegeneration diseases including AD as the Merbl lab identified that the ubiquitin-proteasome system is required for Golgi fragmentation.
My goal is to identify regulatory mechanisms of ubiquitin E3 ligases that are involved in Golgi fragmentation in neurons. Specifically, I aim to identify critical determinants that regulate Golgi homeostasis and integrity under changing pH and calcium concentration and decipher their role in AD using CRISPR gene manipulation, pH-dependent immunofluorescence and biochemical methods and state-of-the-art proteomic and glycomic techniques. Elucidating ubiquitin-dependent regulation of Golgi fragmentation in neurodegeneration and AD would advance our understanding not only of Golgi biology and provide new possibilities for therapeutic intervention for neurodegeneration.

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Coordinator

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution
€ 185 464,32
Address
Herzl street 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Other funding
€ 0,00