"We aim to understand the interplay between autophagy and neurodegeneration better and to identify pathways enabling autophagy upregulation that may have therapeutic utility." David Rubinsztein
UK DRI Group Leader
From a background in medicine, David Rubinsztein became Professor of Molecular Neurogenetics at the University of Cambridge in 2005. Obtaining his PhD from the University of Cape Town, he went on to lead the way in research of autophagy in neurodegenerative disease, with his lab discovering its role in intracytoplasmic aggregate-prone proteins. Author of more than 300 scientific papers, he has received numerous awards, including the Thudichum Medal (Biochemical Society) for outstanding contributions to neuroscience, the Roger de Spoelberch Prize, membership of EMBO, and fellowships of the Royal Society and the Academy of Medical Sciences.
1. At a glance
Targeting the cell’s recycling system to treat dementia
Neurodegenerative diseases are caused by a progressive loss of function and eventual death of neurons within the central nervous system – leading to a range of devastating symptoms, such as difficulties with movement or dementia, which get worse over time.
All cells need to get rid of their waste materials, such as worn-out or damaged protein molecules or machinery. But if a key process in the cell’s recycling system, autophagy, is not working properly in neurons, this can contribute to the build-up of abnormal proteins in the brain - a hallmark of many neurodegenerative conditions, including Alzheimer’s, Parkinson’s and Huntington’s diseases.
Prof David Rubinsztein is using cutting-edge genetics and cell biology to identify new molecular mechanisms involved in regulating autophagy in neurons. His team are building on their previous encouraging results showing that targeting autophagy with drugs can improve the clearance of proteins and help protect neurons from death in experimental systems. He hopes his work will reveal enticing new targets for the development of effective new treatments for neurodegenerative diseases – as well as provide important new insights into how they are triggered in the first place.
2. Scientific goals
(Macro)autophagy is a major route for the degradation of intracytoplasmic contents, including proteins and organelles, like mitochondria. The earliest morphologically recognisable autophagic intermediates are phagophores, which evolve into double-membraned, sac-shaped structures. After phagophore edges extend and fuse, engulfing a portion of cytoplasm, they become autophagosomes, which deliver their contents to lysosomes for degradation.
Autophagy is critical for the degradation of diverse toxic intracytoplasmic aggregate-prone proteins that cause neurodegenerative diseases, including Huntingtin (Huntington’s Disease (HD)), mutant alpha-synuclein (forms of Parkinson’s disease (PD)), and tau (Frontotemporal Dementia (FTD)/Alzheimer’s Disease (AD)). Prof David Rubinsztein and his team have already discovered that autophagy-upregulating drugs enhance the clearance of such proteins and thereby attenuate their toxicities in model systems.
In this UK DRI programme, David will extend on his previous work by using cutting-edge strategies to identify novel autophagy-inducing pathways and validate their benefits in disease models, using two complementary approaches. The neuroprotective effects of the most promising autophagy-inducing pathway identified from these studies will be assessed in HD mouse models.
In the first approach, the team will discover novel pathways that regulate autophagy via transcription and protect against neurodegenerative insults.
Secondly, they will pursue their discovery of a non-canonical signalling pathway regulating autophagy to identify novel regulatory nodes. Canonical autophagy signalling is mediated by phosphatidylinositol 3-phosphate (PI(3)P), the product of class III PI3 kinase, VPS34. PI(3)P recruits specific autophagic effectors like WIPI2, which in turn, recruits ATG16L1 to specify the sites of autophagosome biogenesis. The laboratory recently showed that PI(5)P regulates autophagy via PI(3)P effectors like WIPI2 even in the absence of PI(3)P, and thereby identified a mechanism for forms of non-canonical autophagy signalling.
Main objectives and research goals:
1. To discover novel pathways that regulate autophagy via transcription.
2. To pursue their discovery of a non-canonical signalling pathway regulating autophagy to identify novel regulatory nodes. Identifying and characterising signalling pathways and effectors for the PI(5)P autophagy pathway, and use state-of-the-art cell biology approaches and model systems.
3. Team members
Dr Vicky Barratt (Postdoctoral Fellow)
Dr So Yeong Cheon (Postdoctoral Fellow)
Dr Marian Fernandez (Postdoctoral Fellow)
Dr Angeleen Fleming (Postdoctoral Fellow)
Dr Motoki Fujimaki (Postdoctoral Fellow)
Dr Hee-Yeon Jeon (Postdoctoral Fellow)
Dr Hyunjeong Kim (Postdoctoral Fellow)
Dr Ana Lopez Ramirez (Postdoctoral Fellow)
Dr Sandra Malmgren Hill (Postdoctoral Fellow)
Dr Marco Manni (Postdoctoral Fellow)
Dr So Jung Park (Postdoctoral Fellow)
Dr Claudia Puri (Postdoctoral Fellow)
Dr Gentzane Sanchez Elexpuru (Postdoctoral Fellow)
Dr Ji Hyun Shin (Postdoctoral Fellow)
Dr Farah Siddiqi (Postdoctoral Fellow)
Dr Son Sungmin (Postdoctoral Fellow)
Dr Sylwia Tyrkalska (Postdoctoral Fellow)
Dr Mariella Vicinanza (Postdoctoral Fellow)
Dr Julien Villeneuve (Postdoctoral Fellow)
Dr Sarah Williams (Postdoctoral Fellow)
Dr Dylan Windell (Postdoctoral Fellow)
Dr Lidia Wrobel (Postdoctoral Fellow)
Dr Eleanna Stamatakou (Postdoctoral Fellow)
Ms Jean Thompson (Research Assistant)
Alvin Djajadikerta (PhD Student)
Cansu Karabiyik (PhD Student)
Swati Keshri (PhD Student)
Ingrid Lager Gotaas (PhD Student)
Ryan Prestil (PhD Student)
Laura Ryan (PhD Student)
Ye Zhu (PhD Student)
Within UK DRI:
- Dr Emmanouil Metzakopian, UK DRI at Cambridge
Beyond UK DRI:
- Prof Madan Babu, MRC Laboratory of Molecular Biology
- Dr Jonathan Clarke, The ALBORADA Drug Discovery Institute at the University of Cambridge
Autophagy, proteostasis, Huntington’s disease, tau, Parkinson’s disease
Genome-wide CRISPR/Cas9 genetic screening, zebrafish models, high throughput drug screening
7. Key publications
M Vicinanza, VI Korolchuk, A Ashkenazi, C Puri, FM Menzies, JH Clarke, DC Rubinsztein (2015) PI(5)P regulates autophagosome biogenesis. Molecular Cell 57:219-234.
M Jimenez-Sanchez, W Lam, M Hannus, B Sönnichsen, S Imarisio, A Fleming, A Tarditi, F Menzies, T Ed Dami, C Xu, E Gonzalez-Couto, G Lazzeroni, F Heitz, D Diamanti, L Massai, VP Satagopam, G Marconi, C Caramelli, A Nencini, M Andreini, GL Sardone, NP Caradonna, V Porcari, C Scali, R Schneider, G Pollio, CJ O’Kane, A Caricasole and DC Rubinsztein (2015). siRNA screen identifies QPCT as a druggable target for Huntington’s disease. Nature Chemical Biology 11:347-354
A Ashkenazi, CF Bento, T Ricketts, M Vicinanza, F Siddiqi, M Pavel, F Squitieri, MC Hardenberg, S Imarisio, FM Menzies & DC Rubinsztein (2017) Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545:108-111
C Puri, M Vicinanza, A Ashkenazi, MJ Gratian, Q Zhang, CF Bento, M Renna, FM Menzies and DC Rubinsztein (2018) The RAB11A-positive compartment is a primary platform for autophagosome assembly mediated by WIPI2 recognition of PI3P-RAB11A. Developmental Cell 45: 114-131.
SM Son, SJ Park, H Lee, F Siddiqi, JE Lee, FM Menzies & DC. Rubinsztein (2019) Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metabolism 29:192-201
FH Siddiqi, FM. Menzies, A Lopez, E Stamatakou, C Karabiyik, R Ureshino, T Ricketts, M Jimenez-Sanchez, MA Esteban, L Lai, MD Tortorella, Z Luo, H Liu, E Metzakopian, HJR Fernandes, A Bassett, E Karran, BL Miller, A Fleming and DC Rubinsztein (2019) Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nature Communications 10:1817