The UK DRI at King's College London presents an ambitious and interactive portfolio of research programmes.
Professor Chris Shaw, Professor Of Neurology
UK DRI Associate Director
My team will map out the earliest molecular events that promote TDP-43 mislocalisation and aggregationand the endogenous proteostatic neuroprotective response in patient iPS neurons carrying a range ofproteostatic gene defects and three different lines of TDP-43 transgenic mice. Key degenerative andprotective signatures will be validated in human post-mortem tissues. Armed with a greater understanding ofthe factors that promote TDP-43 aggregation and regulate its clearance we will seek to manipulate thesepathways using gene knockdown/overexpression and small molecules in order to develop a rationaltherapeutic strategy aimed at preventing aggregation and enhancing endogenous proteostasis.
Professor Kei Cho, Prodessor of Neuroscience
UK DRI Programme Lead
My research programme attempts to reveal the pathophysiology of Alzheimer’s disease (AD). Central to this is the weakening of synaptic connections and ultimately their elimination, which is thought to correlate with disease severity. Synapse weakening is therefore fundamental in AD pathogenesis and an important therapeutic target. We have shown that specific signal cascades (e.g., amyloid-beta, caspase, GSK-3 and phosphorylation of tau) underlie synapse weakening and are necessary to induce weakening of AMPA receptor mediated excitatory synaptic transmission. The focus of this programme is therefore to explore a key question: which factors modulate the cellular and molecular mechanisms of ‘synapse weakening’ during dementia-associated pathology? Using innovative gene-transcription regulation and neurophysiology approaches, we will determine whether and how functional/morphological synapse weakening is a critical step in the early pathophysiology of dementia.
Dr Sarah Mizielinska, Lecturer in Dementia
UK DRI Programme Lead
My research group investigates the molecular and cellular mechanisms involved in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), with the aim of better understanding the causes of dementia and neurodegeneration and ultimately providing new and effective targets for disease therapy.
Our research explores how nucleocytoplasmic transport is affected in FTD/ALS at the single molecule level, and how this links to common disease pathologies. Studies focus on disease-associated proteins containing low complexity domains, such as the toxic dipeptide repeat proteins identified pathologically in individuals carrying C9orf72 mutations or TDP-43. This multidisciplinary work utilises super-resolution microscopy to investigate the dynamics of single molecule cargo through the nuclear pore combined with biophysical studies to study phase transitioning of nuclear pore selection barriers to unveil unique disease pathomechanisms often overlooked from bulk endpoint analyses.
We have a keen interest in developing new methodologies and quantitative analyses, particularly in novel and super-resolution imaging technologies.
Professor Annalisa Pastore, Professor of Molecular Basis of Neurodegeneration
UK DRI Programme Lead
My group is interested in studying the structure and function of proteins linked to neurodegenerative diseases in the attempt of understanding the events which lead to pathology and designing suitable therapeutic strategies. We focus on two distinct but converging families of diseases.
We study proteins involved in diseases caused by protein aggregation and misfolding, such as Huntington’s chorea, Machado-Joseph disease and other types of spinocerebellar ataxias. We are interested in mitochondrial pathologies linked to misfunctioning of iron metabolism, such as Friedreich’s ataxia. Our approach uses different complementary biophysical, biochemical and bioinformatics techniques which range from various spectroscopies, to AFM, EM and ITC calorimetry.
We are interested in structural, functional, evolutionary and thermodynamics aspects. We have made important contributions to understand the cellular role of frataxin in iron-sulfur cluster biogenesis as a regulator of the reaction speeds. We have also been the first to describe the interaction between frataxin and the IscS/IscU complex, central to the highly conserved machinery devoted to iron sulphur cluster assembly. In a different project we have proved that protein aggregation is the dark side of protein function. This knowledge will be used for drug design for the treatment of misfolding diseases.
Professor Lawrence Rajendran
UK DRI Deputy Associate Director and Programme Lead
Amyloid-β (Aβ) peptide accumulation into cerebral extracellular plaques is causatively associated with Alzheimer's disease (AD). However, mechanisms that mediate the pre-pathological state of amyloid plaque formation remain elusive. My lab will investigate how nutrient sensing and signaling mechanisms play dual roles in neurons and microglia. Nutrient signaling regulates lysosomal clearance in the neurons thus affecting amyloid formation while the same pathway controls pruning of synapses by microglia. Our findings suggest that both genetic and non-genetic mechanisms could contribute to amyloid clearance and synaptic pruning, which could regulate the risk of developing AD.
Priv.-Doz., Dr Marc-David Ruepp
UK DRI Programme Lead
My research group is interested in RNA metabolism in health and disease with a specific focus on dysfunctional RNA metabolism and neurodegeneration. Our principal objective is to elucidate the molecular basis of selective neuronal death in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). To this end, using CRISPR/Cas9 and TALENs, we have generated a series of isogenic induced pluripotent stem cells harbouring mutations in different genes. We are using these to identify common and, hence, key degenerative pathways responsible for motor neuron death that hopefully can be targeted to modify disease progression, independent of aetiology. Furthermore, based on the conviction that understanding the physiological function(s) of a gene involved in neurodegeneration is valuable to gain insight into potential pathomechanisms, we are interested in elucidating and characterising the functions and RNA targets of Fused in Sarcoma (FUS).