Imperial College London

DrYuYe

Faculty of MedicineDepartment of Brain Sciences

Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 5484yu.ye1 Website

 
 
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Location

 

Sir Michael Uren HubWhite City Campus

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Summary

 

Overview

Aggregation of amyloidogenic proteins, such as tau and alpha-synuclein, are implicated in Alzheimer's and Parkinson's disease, respectively. Removal of these toxic protein aggregates to reduce cell stress is important to prevent progression of the neurodegenerative processes. While much research has focused on how aggregates are assembled, relatively little is known about the reverse process of aggregate removal. The ubiquitin-proteasome system (UPS) is responsible for selective protein degradation, thus preventing aggregate formation. Our recent research has further suggested that proteasomes may also target aggregates in vitro (Cliffe et al.) and in model mammalian cell lines (Zhang et al.). Single-cell patch-clamp and nanopipette aggregate delivery methods further found that cellular proteasomes actively respond to cell stress in a cytoskeleton-dependent manner (Zhang et al).Detection of changes in aggregate level after proteasome treatmentUsing a multi-disciplinary approach that combines state-of-the-art fluorescence microscopy with CRISPR-Cas9 gene-editing techniques, neurobiology approaches and established proteasome biochemistry, our research direction is uniquely placed to investigate how proteasomes maintain cell homeostasis by targeting aggregates at distinct localisations. 

The main objective of our research programme is to investigate proteasomal activity and function in response to cell stress to restore homeostasis. 

The activity of proteasomes controls a wide range of processes including DNA repair, immune system activation, cell cycle and prevention of protein aggregation. It is currently unclear how proteasomes respond to cell stress and damage. Proteasomes are traditionally thought to diffuse throughout the cell to selectively degrade proteins and maintain homeostasis. Others and our recent data have further suggested that proteasome localisation can also be dynamic in space and in time, and translocation may occur through both diffusion and active transport. Despite the importance of proteasome dynamics in cells and the various regulatory roles associated with the proteasome, little is known about the biological mechanisms and associated protein partners that help to drive proteasome translocation to target its substrate. Proteasome distribute with aggregate-induced stress

Our current research evolves around the following topics:

  • What are the factors that recruit proteasomes to distinct cellular locations and their functional role?
  • How are proteasomes transported inside neurons and when aggregates are present? 
  • Which are the proteasomal responses to proteotoxic stress upon aggregate entry? 


In plain English

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Balance is key to a healthy life. Cells balance synthesis of new proteins with removal of proteins whose functions are no longer required. Brain cells sometimes behave abnormally when obsolete proteins assemble together and disrupt normal biological functions. Such harmful agents are implicated in neurodegeneration and dementia. While much research effort has focused on how these agents form, the reverse process of their removal is not well-understood. ‘Proteasomes’ are molecular machines responsible for removing proteins in cells, and their malfunction has been linked to both Alzheimer’s and Parkinson’s disease progression. 
      Our multi-disciplinary research applies state-of-the-art microscopy and biological approaches to look at how toxic agents are cleared inside patient-derived cells. We aim to characterise novel routes to clear toxic agents at distinct neurodegenerative stages, and to understand the molecular mechanisms when the clearing functions are compromised in disease. Ultimately, our research seeks to identify therapeutic points of intervention to reverse the processes that enable neurodegeneration to advance into the various stages of disease. 

Selected Publications

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*Corresponding author



Morten M, Sirvio L, Mee Hayes E, Franco A, Radulescu C, Rupawala H, Ying L, Barnes SJ, Muga A, Ye Y*.Quantitative super-resolution imaging of pathological aggregates reveals distinct toxicity profiles in different synucleinopathies. (Proc Natl Acad Sci U S A in press)

Zuo Y, Jiang K, Chong BK, Finley D, Klenerman D, Ye Y*. ­­A general in vitro assay for studying enzymatic activities of the ubiquitin system. Biochemistry. 2020 59 (7), 851-861

Zhang Y$, Lee JE, Lippert A, Carr A, Ponjavic A, Finley D, Klenerman D, Ye Y*$. Dynamic translocation of proteasomal particles on the cytoskeleton regulated by membrane potential.  (BioRxiv) doi:10.1101/487702

Ye Y*, Klenerman D, Finley D. N-terminal ubiquitination of amyloidogenic proteins triggers removal of their oligomers by the proteasome holoenzyme. Journal of Molecular Biology (In Press)

Cliffe R$, Sang JC, Jiang K, Kundel F, Finley D*, Klenerman D*, Ye Y*$, Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme. Cell Reports. 2019 Feb 19;26(8):2140-2149.

Ye Y, Blaser G, Horrocks M, Ruedas-Rama MJ, Ibrahim SM, Zhukov A, Orte A, Klenerman D*, Jackson SE*, Komander D*, Ubiquitin chain conformation regulates recognition and activity of interacting proteins. Nature. 2012 Dec 13;492(7428):266-270.

Technology and Inventions

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Ubiquitination system ODE simulator (USOS).
Simulation of ubiquitination chain reaction in silico was generated by combining a rational design of ordinary differential equations and computational inference using a machine learning approach. (From Zuo et al. 2019). Github link.

Fluorescent-labelled diubiquitin substrate for a deubiquitinase assay.
Ye Y, Komander D. Patent: WO/2011/157982A1; US 20130102012A1; EP2580344A1

“Y-robot peptide designer”
(2008) sold to Everest Biotech Ltd. for £ 2 000
I wrote PeptideDesigner, automating antigenic peptide design for antibody production. This software increased the success rate of antibody specificity.

Guest Lectures

Harvard-Shanghai Conference on Brain Health - a special meeting for understanding and intervention of Alzheimer’s disease, Harvard Center, Shanghai, 2018

Targeting protein aggregates with the proteasome holoenzyme, Zhejiang University, Hangzhou, 2018

Research Staff

Lines,G

Mee Hayes,E

Morten,M

Rupawala,H

Research Student Supervision

Burridge,M, Immunoproteasomes in tauopathies

Sirvio,L, Post-translational modifications of amyloid proteins for proteasomal degradation