"We aim to gain new understanding of synapse regeneration mechanisms that will provide new targets for therapy." Giovanna Mallucci
UK DRI Associate Director

Giovanna Mallucci is Associate Director of the UK DRI at the University of Cambridge, where she is the van Geest Professor of Clinical Neurosciences. Her pioneering, paradigm-shifting work on common pathogenic mechanisms in neurodegeneration has been instrumental in changing our approach to understanding and treating dementia. Her discoveries around the role of the unfolded protein response (UPR) and its pharmacological manipulation in these disorders were hailed as a “turning point in search for medicines to control and prevent Alzheimer’s”. More recently, her lab has pursued the understanding of mechanisms of synapse regeneration to prevent neurodegeneration, which is the focus of her DRI research programme. She is an ERC Consolidator Fellow and a Fellow of the Academy of Medical Sciences. A practicing neurologist specialising in dementia, she bridges the lab and clinic and has established a new Translational Research Unit within the UK DRI at Cambridge to accelerate translation of basic research findings into patients.

1. At a glance

Protecting the connections between neurons in early stages of dementia

In healthy adult brains, the connections between brain cells (known as synapses) are continuously lost and replaced. However, excessive loss of synapses is an early feature in several neurodegenerative diseases, which include Alzheimer’s and Parkinson’s diseases – and eventually leads to the death of brain cells. Therefore, finding ways to stop, slow down or reverse this process offers exciting opportunities for preventing and treating dementia.

Professor Mallucci aims to increase our understanding of the biological mechanisms involved in the loss and repair of synapses in health and disease. Her team is particularly focussed on the role of a key protein called RBM3 – and its binding partner RTN3. She has already discovered that boosting both RBM3 and RTN3 prevents synapses from degenerating, dramatically improving memory, survival of brain cells and increasing life-span in mouse models of neurodegeneration. So, targeting this pathway could provide an effective new avenue for treating neurodegenerative diseases.

Giovanna’s team will use a combination of cutting-edge techniques, as well as drug screens, to study the role of these proteins and find new ways of manipulating their levels in the brain. Targeting these early changes in disease progression may be the most effective way to slow decline in neurodegenerative conditions.

2. Scientific goals

Synapse loss underlies the earliest symptoms in several neurodegenerative diseases; its progression eventually leads to neuronal loss. Critically, it is the early stages in pathogenesis that can be rescued and therefore, a key therapeutic target window for intervention.

In the healthy adult brain synapses are continually lost and replaced, through structural plasticity, a process critical for repair that also underlies learning and memory. Mallucci’s team has shown that neurodegeneration results, at least in part, from a failure of structural synaptic plasticity early in the disease process. Using the paradigm of cooling-induced structural plasticity that occurs in hibernation in prion disease and Alzheimer's disease (AD) mouse models, Giovanna Mallucci and her team have: 1) shown that the capacity for synaptic repair and reassembly is impaired 2) found that this results from failure to induce the cold shock protein, the RNA chaperone: RNA binding motif 3 (RBM3) 3) defined the major role of RBM3 in maintaining structural plasticity and driving synaptic repair. Critically, they also demonstrated the therapeutic potential of manipulation of RBM3 levels for neuroprotection. Thus, RBM3 induction is profoundly neuroprotective, rescuing cognitive deficits and markedly increasing survival in prion and AD mouse models. Most recently, however, the team investigated the RNA chaperone function of RBM3. They discovered that on cooling, RBM3 induces and binds RTN3, a reticulon protein implicated in dendritic spine and synapse formation and that this is a major effector of RBM3-mediated and cooling-induced neuroprotection.

RBM3 is expressed in human brain tissue and its expression increases upon hypothermia, highlighting the potential relevance of this pathway in both pathogenesis and therapy in neurodegenerative disease.

Main objectives and research goals:

Understanding why the RBM3-RTN3 mediated protective response fails in neurodegenerative diseases and devising ways to induce this pathway as a new therapeutic strategy is the focus of this interdisciplinary programme. Their aims are to investigate:

1. Upstream signalling of RBM3 and why this fails to be induced in neurodegeneration using a variety of biophysical and cell biological methods.

2. Cell biology of RBM3 and RTN3 and their actions using in vitro and in vivo approaches.

3. Therapeutic modulation of RBM3 and RTN3 using in vitro and in vivo approaches.

4. Synaptic protein dynamics in structural plasticity and local effect of RBM3/RTN3 using super-resolution imaging.

This programme runs in parallel to Giovanna’s other major programme focused on understanding the role of the unfolded protein response (UPR) in neurodegeneration and manipulating this for therapy.

3. Team members

Dr Hector Albert-Gasco (Postdoctoral Fellow)
Dr Gonca Bayraktar (Postdoctoral Fellow)
Dr Adrian Butcher (Postdoctoral Fellow)
Dr Fei Gao (Postdoctoral Fellow)
Dr Mark Halliday (Postdoctoral Fellow)
Dr Andrew Harrison (Postdoctoral Fellow)
Dr Daniel Hughes (Postdoctoral Fellow)
Dr Diego Peretti (Postdoctoral Fellow)
Dr Heather Smith (Postdoctoral Fellow)
Dr Emad Sidhom (Postdoctoral Fellow)
Dr Julie Qiaojin Lin (Henry Wellcome Fellow)
Dr Dhruv Panchal (Wellcome Clinical Training Fellow)
Samantha Farrow (Lab Supervisor)
Joseph Hayes (Research Assistant)
Lis De Weerd (Research Assistant)
Dr Dean Swinden (Technician)
Ibrahim Humoud (PhD Student)
Karinder Brar (PhD Student)
Julia Zbiegly (PhD Student)

Kara Gnodde Translational Neuroscience Unit
Based at Windsor Research Unit to deliver experimental medicines studies and clinical trials

Dr Emad Sidhom (Clinical Fellow)
Dr Ben Underwood (Consultant Psychiatrist for Elderly; Clinical Lead)
Vusile Vince Mlilo (Clinical Research Nurse)

4. Collaborations

Within UK DRI:

Dr Edward Avezov, UK DRI at Cambridge
Dr Emmanouil Metzakopian, UK DRI at Cambridge
Prof David Rubinzstein, UK DRI at Cambridge
Prof Clemens Kaminski, UK DRI at Cambridge
Prof Henrik Zetterberg, UK DRI at UCL

Beyond UK DRI:

Dr Jernej Ule, The Francis Crick Institute, UK
Prof Christine Holt, University of Cambridge, UK
Prof Anne Willis, MRC Toxicology Unit, University of Cambridge, UK
Prof Owen Sansom, Beatson Cancer Institute, Glasgow, UK
Prof Mark Smales and Dr Tobias van der Haar, University of Kent, UK
Dr Michael Bollong, Scripps Institute, La Jolla, CA, USA
Prof David Rowitch, University of Cambridge, UK and UCSF, CA, USA
Prof Franklin Aigbirhio and Dr Tim Fryer, Wolfson Centre for Brain Imaging, University of Cambridge, UK
Prof John O’Brien, University of Cambridge, NIHR BRC, UK
Prof Sadaf Farooqi, CIMR and IMS, University of Cambridge, UK
Prof David Ron, CIMR, University of Cambridge, UK
Prof Peter Fischer, University of Nottingham, UK
Prof David Barrett, University of Nottingham, UK
Prof Erin Schuman, Max Plank Institute for Brain Research, Germany
Prof Paolo Salomoni, DZNE, Bonn, Germany

5. Topics

Super-resolution microscopy (including SPT, STORM, SIM, TIRF), biophysical and cell biological methods, molecular biology methods; CRISPR/cas9 gene editing; in vivo mouse models; virally-mediated genetic modulation; drug screening; structural biology methods; PET imaging in humans and mice

6. Techniques

7. Key publications

Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Halliday M, Radford H, Zents KAM, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M and Mallucci GR. Brain 2017, 140(6):1768-1783. doi: 10.1093/brain/awx074.

Scientific commentary Brain (doi:10.1093/brain/awx107)
Research Highlights Nature Reviews Neurology
Press: BBC News

Oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice. Moreno JA, Halliday M, Molloy C, Axten JM, Willis AE, Ortori CA, Barrett DA, Fischer PM and Mallucci GR. Science Translational Medicine 2013, 5,206ra138

4 citations in F1000 Prime 2013
Research highlights: Nature Reviews Neurology, Science Translational Medicine, Movement Disorders, Alzforum
Press: BBC/CNN/ITV/Al Jazeera/ABC/SkyNews/newspapers worldwide; BBC News Medical Science Highlights of 2013

Sustained translational repression by eIF2α−P mediates prion neurodegeneration. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Guerra Martin M, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, M Bushell and Mallucci GR. Nature 2012, 485, 507-11.

3 citations in F1000 Prime 2012
Commentary: Movement Disorders

RBM3 mediates structural plasticity and the protective effects of cooling in neurodegenerative disease. Peretti D, Bastide A, Verity N, Guerra Martin M, Molloy C, Moreno JA, Radford H, Steinert J, Dinsdale D, Willis AE and Mallucci GR. Nature 2015 518(7538):236-9. doi: 10.1038/nature14142

News and Views: Nature, 2015, 518(7538):177-8;
Research highlights: Nature Reviews Neurology; Nature Reviews Neuroscience; Alzforum;
Press: BBC News

RTN3, a novel cold-induced protein, mediates the neuroprotective effects of RBM3. Bastide A, Peretti D, Knight JRP, Grosso S, Spriggs RV, Pichon X, Sbarrato T, Roobol A, Roobol J, Vito D, Bushell M, von der Haar T, Smales CM, Mallucci GR* and Willis AE*. Current Biology 2017 27(5):638-650. doi: 10.1016/j.cub.2017.01.047

Giovanna Mallucci