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Deciphering ubiquitin-dependent regulation of Golgi homeostasis control in neurodegeneration

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.

Field of science

  • /medical and health sciences/basic medicine/physiology/homeostasis
  • /natural sciences/chemical sciences/inorganic chemistry/inorganic compounds
  • /medical and health sciences/basic medicine/neurology/alzheimer

Call for proposal

H2020-MSCA-IF-2018
See other projects for this call

Funding Scheme

MSCA-IF-EF-ST - Standard EF

Coordinator

WEIZMANN INSTITUTE OF SCIENCE
Address
Herzl Street 234
7610001 Rehovot
Israel
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 185 464,32