Deciphering ubiquitin-dependent regulation of Golgi homeostasis control in neurodegeneration

Project Information

UbiGolD

Grant agreement ID: 845066

DOI

10.3030/845066

Project closed

EC signature date 25 March 2019

Start date 1 April 2019

End date 31 March 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 185 464,32

EU contribution

€ 185 464,32

Coordinated by

WEIZMANN INSTITUTE OF SCIENCE
Israel

Periodic Reporting for period 1 - UbiGolD (Deciphering ubiquitin-dependent regulation of Golgi homeostasis control in neurodegeneration)

Reporting period: 2019-04-01 to 2021-03-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In this work we examined ubiquitin-dependent mechanisms that are involved in Golgi fragmentation in neurons. Specifically, in objective 1 we identify critical determinants that regulate Golgi homeostasis and also can be affected under Golgi stress. In response to objective 2, we found that the Zinc finger protein-like 1 (ZFPL1) is a crucial E3 ligase for Golgi homeostasis maintenance. in objective 3, 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. Further understanding of the identified substrates may offer, in the future, new possibilities for therapeutic intervention for AD and neurodegeneration.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

During the fellowship period, Dr. Shmueli acquired new abilities on research techniques and transferable skills, which help her to accomplish her major objective of establishing her being a leader of an independent research group. Dr. Shmueli had specialized in proteomic and PTM research that led to the opening of a new unit under the Merbl lab in which Dr. Shmueli will be leading. The goal of this unit is to develop into a clinical proteomic center that will help with finding new therapeutic approaches for a wide array of clinical and biological conditions.
This study describing aberrations of Golgi integrity in AD, together with the new findings from Dr. Merbl’s lab of a Golgi-specific ubiquitin-dependent stress response strongly suggests that regulation of Golgi homeostasis may play a major role in neurodegeneration in particular in AD. A cure to prevent the onset or delay of the progression of the pathology of AD does not exist, to date, and it is urgently needed to ensure healthy aging of the European population. We are now elucidating the regulatory mechanisms and pathways involved in Golgi regulation in AD focusing on ZFPL1 protein as a target, which may therefore offer novel therapeutic intervention for AD and neurodegenerative diseases. In conclusion, the fellowship period was highly beneficial for the applicant’s career advancement and it will clearly contribute to the excellence of the European Research Area.

Schematic representation of the project main aims.