UbiGolD · Deciphering ubiquitin-dependent regulation of Golgi homeostasis control in neurodegeneration
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-04-01 → 2021-03-31
- EU contribution
- €185,464
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Deciphering ubiquitin-dependent regulation of Golgi homeostasis control in neurodegeneration
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 largely unknown and preventive treatment is not yet available. Lately, the ubiquitin-proteasome system as well as Golgi fragmentation were observed in neurodegenerative disorders and linked to AD. In this work we aimed to identify the regulatory mechanisms of E3 ligases that are involved in fragmentation of the Golgi apparatus in neurons. Specifically, our goal was to identify ubiquitin-dependent determinants that regulate Golgi homeostasis and integrity under the Golgi stress and characterize their involvement in AD. We intend to do so by three interconnected yet independent aims/objectives: (a) Identify ubiquitin E3 ligases that are involved in response to Golgi stress (b) Decipher the cellular role of putative Golgi-related E3s in AD using molecular, biochemical and cellular systems (c) Determine the effects of perturbation of Golgi-associated E3 ligases in vivo. Specifically, we identify critical determinants that regulate Golgi homeostasis and also can be affected under Golgi stress. We reveald the Zinc finger protein-like 1 (ZFPL1) as a crucial E3 ligase for Golgi homeostasis maintenance. Also, using state-of-the-art proteomic and glycomic approaches, we mapped the PTM landscape (Ub and glycosylation state) in cerebral spinal fluid (CSF) of different neuronal pathologies and revealed differential PTM patterns that are associated with different physiological states. Thus, our work highlights novel PTMs that are associated with AD and identified a novel E3 ligase that is involved in Golgi fragmentation in neurodegeneration and AD, which we will further examine to determine its role in controlling Golgi homeostasis and neurodegeneration.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- WEIZMANN INSTITUTE OF SCIENCE · RehovotCoordinatorIsrael
Links
Data: CORDIS, © European Union