"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 & Interim Centre Director
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 Beatrice Festa (Postdoctoral Researcher)
Dr Angeleen Fleming (Postdoctoral Researcher)
Dr Hee-Yeon Jeon (Postdoctoral Researcher)
Dr Xinyi Li (Postdoctoral Researcher)
Dr So Jung Park (Postdoctoral Researcher)
Dr Claudia Puri (Postdoctoral Researcher)
Dr Farah Siddiqi (Postdoctoral Researcher)
Dr Sungmin Son (Postdoctoral Researcher)
Dr Eleanna Stamatakou (Postdoctoral Researcher)
Dr Lidia Wrobel (Postdoctoral Researcher)
Dr Ye Zhu (Postdoctoral Researcher)
Alvin Djajadikerta (PhD Student)
Junrui He (PhD Student)
Swati Keshri (PhD Student)
Matea Rob (PhD Student)
Laura Ryan (PhD Student)
Charlotte Ross (Administrator)
Within UK DRI:
- Prof David Klenerman, UK DRI at Cambridge
- Dr Gabriel Balmus, UK DRI at Cambridge
Beyond UK DRI:
- Prof Roger Pocock, Monash
- Prof Alfred Goldberg, Harvard
- Merck, Sharp & Dohme
- Daniel Geschwind, UCLA
- Judith Steen, Harvard
- Steve Haggarty, Harvard
- Alvin Huang, Brown University
Autophagy, proteostasis, Huntington’s disease, tau, Parkinson’s disease
Genome-wide CRISPR/Cas9 genetic screening, zebrafish models, high throughput drug screening
7. Key publications
L Wrobel, SM Hill, A Djajadikerta, M Fernandez-Estevez, C Karabiyik, A Ashkenazi, VJ Barratt, E Stamatakou, A Gunnarsson, T Rasmusson, EW Miele, N Beaton, R Bruderer, Y Feng, L Reiter, MP Castaldi, R Jarvis, K Tan, RW Bürli, and DC Rubinsztein (2022). Compounds activating VCP D1 ATPase enhance both autophagic and proteasomal neurotoxic protein clearance. Nature Communications 13:4146
A Fleming, M Bourdenx, M Fujimaki, C Karabiyik, GJ Krause, A Lopez, A Martín-Segura, C Puri, A Scrivo, J Skidmore, SM Son, E Stamatakou, L Wrobel, Y Zhu, AM Cuervo and DC Rubinsztein (2022). The Different Autophagy Degradation Pathways and Neurodegeneration. Neuron 110:935-966.
C Karibiyik, M Vicinanza, SM Son and DC Rubinsztein (2021) Glucose starvation induces autophagy via ULK1-mediated activation of PIKfyve in an AMPK-dependent manner. Developmental Cell 56:1961-1975.
SM Hill, L Wrobel, A Ashkenazi, M Fernandez-Estevez, K Tan, RW Bürli, and DC Rubinsztein (2021). VCP/p97 regulates Beclin-1-dependent autophagy initiation. Nature Chemical Biology 17:448–455
C Puri, MM Manni, M Vicinanza, C Hilcenko, Y Zhu, G Runwal, E Stamatakou, FM Menzies, K Mamchaoui, M Bitoun and DC Rubinsztein (2020). A DNM2 centronuclear myopathy mutation reveals a link between recycling endosome scission and autophagy. Developmental Cell 53:154-168
C Nehammer, P Ejlerskov*, S Gopal, A Handley, L Ng, P Moreira, H Lee, S Issazadeh-Navikas, DC Rubinsztein* and R Pocock*. (Joint senior author) (2019). Interferon-b-induced miR-1 alleviates toxic protein accumulation by controlling autophagy. eLife 2019;8:e49930.
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
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.
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
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