"The efficacy at which toxic agents are removed before they cause damage is a major determinant of neurodegenerative progression. Our lab uses innovative techniques to understand how toxic agents are recycled at different neurodegenerative stages." Yu Ye
UK DRI Affiliated PI

Dr Yu Ye completed his PhD at MRC-LMB, and held a Junior Research Fellowship and a Sir Henry Wellcome Fellowship at University of Cambridge and Harvard Medical School. Dr Ye aims to untangle the molecular agents causing dementia with the ubiquitin-proteasome system. The Ye lab studies the interplay between the ubiquitin-proteasome system and amyloid proteins in biological systems. Using advanced fluorescence imaging techniques, the lab seeks to uncover the cellular mechanisms of restricting or reversing protein aggregation, and how malfunction of this system leads to neurodegenerative disorders.

1. At a glance

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.

The Ye lab's multi-disciplinary research applies state-of-the-art microscopy and biological approaches to look at how toxic agents are cleared inside patient-derived cells. They 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, this research seeks to identify therapeutic points of intervention to reverse the processes that enable neurodegeneration to advance into the various stages of disease.

2. Scientific goals

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. Dr Yu Ye's 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). Using a multi-disciplinary approach that combines state-of-the-art fluorescence microscopy with CRISPR-Cas9 gene-editing techniques, neurobiology approaches and established proteasome biochemistry, Dr Ye's research direction is uniquely placed to investigate how proteasomes maintain cell homeostasis by targeting aggregates at distinct localisations.

The main objective of his research programme is to investigate proteasome translocation 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. Dr Ye's recent data, and that from others, 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. Dr Ye's current research evolves around the following topics:

1. What are the factors that recruit proteasomes to distinct cellular locations and their functional role?

2. How are proteasomes transported inside neurons and when aggregates are present?

3. Which are the proteasomal responses to proteotoxic stress upon aggregate entry?

3. Team members

Dr Michael Morten (Postdoctoral Researcher)
Matilda Burridge (PhD Student)
Liina Sirvio (PhD Student)

4. Collaborations

Within UK DRI:

Prof David Klenerman, UK DRI at Cambridge
Dr Gabriel Balmus, UK DRI at Cambridge
Dr Tim Bartels, UK DRI at UCL

Beyond UK DRI:

Prof Maria Spillantini, University of Cambridge
Prof Daniel Finley, Harvard Medical School
Dr Liming Ying, Imperial College London

5. Topics

tau, alpha-synuclein, proteasome; protein aggregation, protein degradation, disaggregation, protein homeostasis, proteostasis, ubiquitination, deubiquitination systems

6. Techniques

Advanced fluorescence microscopy, Super-resolution TIRF microscopy, Single-particle tracking, Light-sheet microscopy, CRISPR-Cas9, Ubiquitin-Proteasome System

7. Key publications

Reversing protein aggregation:

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.

Advanced imaging of proteasomes in cells:

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. (under revision) doi:10.1101/487702

Ponjavic A, Ye Y, Laue E, Lee SF, Klenerman D. Sensitive light-sheet microscopy with multiwell plates using an AFM cantilever. Biomed Opt Express 2018 9(12), 5863-5880

Biophysical techniques to study the ubiquitin system:

Zuo Y, Chong BK, Jiang K, Finley DJ, Klenerman D, Ye Y^*. A general in vitro assay to study enzymatic activities of the ubiquitin system. Biochemistry. 2020 Jan 17. doi.org/10.1021/acs.biochem.9b00602

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.

^*corresponding author, ^$equal contribution

8. Lab website

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