Giovanna Mallucci

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Giovanna Mallucci
Congreso Futuro - 2019-01-15 - 02.jpg
Born (1963-06-29) 29 June 1963 (age 59)
Alma mater St Hilda's College, Oxford
University College London
Imperial College London
Known formechanisms of neurogenerative diseases; translational neuroscience
Awards Potamkin Prize (2021)
Scientific career
Fields Neuroscience
Neurodegeneration
Prion diseases
Institutions University of Cambridge
University of Leicester
Thesis Prion protein gene knockout in the mouse using the Cre/1oxP system  (2001)

Giovanna Rachele Mallucci (born 29 June 1963) is van Geest Professor of Clinical Neurosciences at the University of Cambridge in England and associate director of the UK Dementia Research Institute at the University of Cambridge. She is a specialist in neurodegenerative diseases. [1] [2] [3] [4]

Contents

Biography

Giovanna Mallucci attended Haberdashers' Aske's School for Girls, Elstree before studying medicine at St Hilda's College, Oxford, and University College London, [5] then specialized in neurology. She gained her Ph.D. in 2001 from Imperial College, London, for her work on transgenic models of prion disease, after which she combined scientific and clinical careers. In 2008, she joined the MRC Toxicology Unit as Programme Leader, focusing on generic mechanisms of neurodegeneration. In 2014, she was elected van Geest Professor of Clinical Neurosciences at the University of Cambridge and in 2017 was awarded the Cambridge Centre of UK Dementia Research Institute of which she is the director. She is an Honorary Consultant Neurologist at Addenbrooke's Hospital, [6] with a specialist interest in dementia.

Mechanisms of neurotoxicity

Her background is in modeling prion diseases in mice, looking at mechanisms of neurotoxicity, and developing new therapeutic approaches. Her group has shown that early synaptic changes in mice with prion disease can be reversed, resulting in the recovery of synaptic and cognitive function and behavioral deficits, long term neuroprotection, and lifelong survival of affected animals. Thus neurodegeneration can be prevented by reversing early synaptic deficits.

Their program uses several model systems – mice (wild type and transgenic), the primary neurons, and the nematode C. elegans, to understand the early molecular events that cause synaptic toxicity and neuronal cell death in neurodegeneration. In parallel, they are looking at the mechanisms involved in synaptic repair processes.

Her [7] lab is interested in understanding mechanisms of neurodegeneration. The central theme is the identification of common pathways across the spectrum of these disorders (which include Alzheimer's and related diseases) that are relevant for both mechanistic insights and therapy. They focus both on 'toxic' processes that can be targeted to prevent neuronal death, and on regenerative processes that can be harnessed for repair. Using mouse models, they described the pathogenic role of the unfolded protein response (UPR) in neurodegeneration, which led to the discovery of the first small molecule - an inhibitor of this pathway - to prevent neurodegeneration in vivo. They also recently discovered the phenomenon of failure of synaptic repair processes in neurodegeneration and the underlying mechanisms: failure of another stress response involving 'cold shock' proteins, which they have successfully harnessed for neuroprotection. They aim to translate this research into new treatments for dementia.

Profession

Mallucci leads the new centre of the UK Dementia Research Institute on Cambridge Biomedical Campus [8] tasked with finding new ways to diagnose, treat, prevent and care for people with dementia.

The centre joins others at Cardiff University, the University of Edinburgh, Imperial College London and King's College London [9] in forming the new UK Dementia Research Institute (UK DRI). [10]

Mallucci said: “The mission of the DRI overall is to take a transformative change in the understanding of the cellular mechanisms that make brain cells go wrong in dementia and degenerative brain disease and discovering new ways of treating based on those insights. In Cambridge we have such world-leading expertise in so many different fields so we are focusing on cross-disciplinary research, integrating chemistry and biophysics along with classic cell biologists such as myself who understand the disease. It's going to be a real dementia hub. There are lots of avenues but what you need is a couple of things that are going to change the course of the disease and Cambridge is very well-positioned for those kinds of discoveries. We have real momentum on some re-purposed drugs.”

It is in this area that a team led by Mallucci has made a potentially significant breakthrough.

Having identified a major pathway that leads to brain cell death in mice, scientists have now found two drugs that block that pathway and prevent neurodegeneration, with minimal side effects in rodents.

One of these drugs – trazodone hydrochloride – is already licensed for use in humans as an antidepressant.

Mallucci said: “The exciting development is that we've bypassed the whole drug discovery pipeline, which can take forever. You don't know what's going to work in humans but it means we don't have to wait 20 years to find something.” She added: “We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer's disease and other dementias. We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders. “Interestingly, trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group. We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.” It is known that misfolded proteins build up in the brains of those with neurodegenerative diseases and are a major factor in dementias such as Alzheimer's and Parkinson's as well as prion disease. [11] The team led by Mallucci at the Medical Research Council's (MRC) Toxicology Unit in Leicester originally discovered that this accumulation of misfolded proteins in mice with prion disease over-activated a natural defense mechanism, 'switching off' the vital production of new proteins in brain cells. Switching protein production back on with an experimental drug halted neurodegeneration but the drug tested was toxic to the pancreas and not suitable for testing in humans. But in a study published in Brain, the researchers revealed how they identified a number of suitable candidates after testing 1,040 compounds from the National Institute for Neurological Disorders and Stroke, initially in worms, which have a functioning nervous system. Testing on mice with prion disease and a form of familial tauopathy or frontotemporal dementia (FTD) identified two drugs that restored the protein production rate. [11]

Work with MRC

A team of MRC scientists, led by Mallucci who a few years ago identified a major pathway that leads to brain cell death in mice, have now found two drugs that block the pathway and prevent neurodegeneration. The drugs caused minimal side effects in the mice and one is already licensed for use in humans, so is ready for clinical trials.

Misfolded proteins build up in the brain in several neurodegenerative diseases and are a major factor in dementias such as Alzheimer's and Parkinson's as well as prion diseases. Previously, the team found that the accumulation of misfolded proteins in mice with prion disease over-activates a natural defense mechanism, 'switching off' the vital production of new proteins in brain cells. They then found switching protein production back on with an experimental drug halted neurodegeneration. However, the drug tested was toxic to the pancreas and not suitable for testing in humans.

In the latest study, published today in Brainopens in new window, the team tested 1040 compounds from the National Institute for Neurological Disorders and Stroke, first in worms (C.elegans) which have a functioning nervous system and are a good experimental model for screening drugs to be used on the nervous system and then in mammalian cells. This revealed a number of suitable candidate compounds that could then be tested in mouse models of prion disease and a form of familial tauopathy (frontotemporal dementia - FTD), both of which had been protected by the experimental - but toxic - compounds in the team's previous studies.

The researchers identified two drugs that restored protein production rates in mice trazodone hydrochloride, a licensed antidepressant, and dibenzoylmethane (DBM), a compound being trialed as an anti-cancer drug. Both drugs prevented the emergence of signs of brain cell damage in most of the prion-diseased mice and restored memory in the FTD mice. In both mouse models, the drugs reduced brain shrinkage which is a feature of neurodegenerative disease.

Giovanna Mallucci, who led the team from the Medical Research Council's (MRC) Toxicology Unit in Leicester and the University of Cambridge, was today announced as one of the five associate directors of the UK Dementia Research Institute. She said:

“We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer's disease and other dementias. We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.

“Interestingly, Trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group. We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.”

The research was funded by the Medical Research Council and Mallucci was also funded by a grant from Alzheimer's Society and Alzheimer's Drug Discovery Foundation.

Rob Buckle, Chief Science Officer at the MRC, said: “This study builds on previous work by this team and is a great example of how really innovative discovery science can quite quickly translate into the possibility of real drugs to treat disease.

“The two drugs identified remain experimental but they were shown to protect the mice even when given after the processes underlying neurodegeneration had become established. We currently have no way of treating these diseases so the prospect of finding drugs that can slow or stop them from progressing is extremely exciting – even more so when this is based on drugs that have already undergone expensive and time-consuming testing in unrelated studies to establish that they are likely to be safe to use in humans.”

Dr. Doug Brown, Director of Research and Development at the Alzheimer's Society, said:

“We're excited by the potential of these findings. They show that a treatment approach originally discovered in mice with prion disease might also work to prevent the death of brain cells in some forms of dementia. This research is at a very early stage and has not yet been tested in people - but as one of the drugs is already available as a treatment for depression, the time taken to get from the lab to the pharmacy could be dramatically reduced.

“The drug blocks a natural defense mechanism in cells which is overactive in the brains of people with frontotemporal dementia, Alzheimer's disease and Parkinson's, so has the potential to work for several conditions. So far it has only been tested in mice with frontotemporal dementia [12] but Alzheimer's Society is now funding the researchers to test it in models of Alzheimer's too.”

Related Research Articles

Prion Pathogenic type of misfolded protein

Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It is not known what causes a normal protein to misfold, but the resulting abnormal three-dimensional structure confers infectious properties by collapsing nearby protein molecules into the same shape.

Lewy body Spherical inclusion commonly found in damaged neurons

Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias, and some other disorders. They are also seen in cases of multiple system atrophy, particularly the parkinsonian variant (MSA-P).

Excitatory synapse Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travel, each neuron often making numerous connections with other cells. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

Tau protein Group of six protein isoforms produced from the MAPT gene

The tau proteins are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.

Amyloid beta Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

PRNP Protein involved in multiple prion diseases

PRNP is the human gene encoding for the major prion protein PrP, also known as CD230. Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughout the body.

Tauopathy Medical condition

Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregates. The mechanism of tangle formation is not well understood, and whether tangles are a primary cause of Alzheimer's disease or play a peripheral role is unknown.

Neurodegenerative disease Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

Proteinopathy Medical condition

In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.

Granulin Protein-coding gene in humans

Granulin is a protein that in humans is encoded by the GRN gene. Each granulin protein is cleaved from the precursor progranulin, a 593 amino acid long and 68.5 kDa protein. While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.

John Quinn Trojanowski was an American academic research neuroscientist specializing in neurodegeneration. He and his partner, Virginia Man-Yee Lee, MBA, Ph.D., are noted for identifying the roles of three proteins in neurodegenerative diseases: tau in Alzheimer's disease, alpha-synuclein in Parkinson's disease, and TDP-43 in Amyotrophic Lateral Sclerosis (ALS) and frontotemporal degeneration.

Clinical neurochemistry

Clinical neurochemistry is the field of neurological biochemistry which relates biochemical phenomena to clinical symptomatic manifestations in humans. While neurochemistry is mostly associated with the effects of neurotransmitters and similarly functioning chemicals on neurons themselves, clinical neurochemistry relates these phenomena to system-wide symptoms. Clinical neurochemistry is related to neurogenesis, neuromodulation, neuroplasticity, neuroendocrinology, and neuroimmunology in the context of associating neurological findings at both lower and higher level organismal functions.

Maria Grazia Spillantini, is Professor of Molecular Neurology in the Department of Clinical Neurosciences at the University of Cambridge. She is most noted for identifying the protein alpha-synuclein as the major component of Lewy bodies, the characteristic protein deposit found in the brain in Parkinson's disease and dementia with Lewy bodies. She has also identified mutations in the MAPT gene as a heritable cause for frontotemporal dementia.

A PERK inhibitor is a small molecule compound that unlike any existing drug inhibits the expression of protein kinase RNA–like endoplasmic reticulum kinase. The inhibitor demonstrated the ability to halt brain cell death in mice with prion disease. It represents a major new pathway for drug research on brain illness, including Alzheimer's disease and Parkinson's disease. The compound works by blocking a faulty signal in brains afflicted by neurodegenerative diseases that shuts down the production of essential proteins, leaving brain cells unprotected and soon dead.

Tara Spires-Jones is professor of neurodegeneration and deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh. She is also programme lead of the UK Dementia Research Institute.

The neuroscience of aging is the study of the changes in the nervous system that occur with ageing. Aging is associated with many changes in the central nervous system, such as mild atrophy of the cortex that is considered non-pathological. Aging is also associated with many neurological and neurodegenerative disease such as amyotrophic lateral sclerosis, dementia, mild cognitive impairment, Parkinson's disease, and Creutzfeldt–Jakob disease.

Mathias Jucker, born 7 July 1961 in Zürich, Switzerland, is a Swiss neuroscientist, Professor, and a Director at the Hertie Institute for Clinical Brain Research of the University of Tübingen, Germany. He is also a Group Leader at the German Center for Neurodegenerative Diseases in Tübingen. Jucker is known for his research on the basic biologic mechanisms underlying brain aging and Alzheimer’s disease.

Elizabeth Mary Claire Fisher is a British geneticist and Professor at University College London. Her research investigates the degeneration of motor neurons during amyotrophic lateral sclerosis and Alzheimer's disease triggered by Down syndrome.

Phenserine

Phenserine is a synthetic drug which has been investigated as a medication to treat Alzheimer's disease (AD), as the drug exhibits neuroprotective and neurotrophic effects.

References

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  5. "Mallucci, Prof. Giovanna Rachele, (born 29 June 1963), Van Geest Professor of Clinical Neurosciences, University of Cambridge, since 2014; Associate Director, UK Dementia Research Institute at University of Cambridge, since 2017; Fellow, Churchill College, Cambridge, since 2018; Hon. Consultant Neurologist, Addenbrooke's Hospital, Cambridge, since 2012." WHO'S WHO & WHO WAS WHO. 1 Dec. 2015
  6. "Addenbrooke's Hospital | Cambridge University Hospitals". www.cuh.org.uk. Retrieved 2017-06-14.
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  9. "King's College London - Home". www.kcl.ac.uk. Retrieved 2017-06-14.
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  12. Choices, NHS. "Frontotemporal dementia - NHS Choices". www.nhs.uk. Retrieved 2017-06-14.