Structural studies of proteins involved in neurodegenerative and muscular diseases 2

Lead Research Organisation: King's College London


The accomplishment of the human genome together with the fast progresses made in gene mapping technology have opened for the first time the possibility of approaching hereditary disorders at a molecular level. We approach the study of human diseases by understanding their structure/function relationship. The role of the molecular structure in modern biology and medicine may be directly appreciated if we consider that structure determination of the DNA, the molecule which contains the whole genetic information, unveiled the secret of life. Our laboratory focuses on determining the 3D structure of proteins with specific interest for proteins involved in neurodegenerative diseases such as the Huntington Chorea, Friedreich ataxia, and Fragile X syndrome and muscular pathologies such as different types of cardio-myopathies. Despite the different symptoms, these diseases, all incurable, share the fact that in affected patients, the proteins encoded by the corresponding genes are produced in altered forms, or in smaller quantity down to their complete absence. By determining the shape of the proteins involved we can then understand the role of these mutations on the protein functions and ultimately design new therapeutical strategies. We use a combination of biochemical and biophysical techniques which help us to reconstruct the cellular role of the proteins of interest and characterise their structure/function relationship.

Technical Summary

We focus on neurodegeneration and muscular pathologies.||A molecular approach to human genetic diseases More than 12 human genetic diseases have been associated with expansions of nucleotide repeats in their corresponding genes, all identified in the last 10 years. These diseases, currently incurable, are interesting both for their impact in the human population and for the unusual pattern of genetic behaviour. They are grouped into two sub-families according to whether the expansion occurs in coding or non-coding regions. In our group we have started an integrated approach which makes use of different biochemical and biophysical techniques to study the structure and function of the proteins encoded by several genes of the trinucleotide expansion family. Amongst them are FMRP, the protein responsible for fragile x and frataxin, the protein involved for Friedreichs ataxia. We want to understand the cellular role of these proteins and describe the mechanism of molecular recognition with their binding partners. We have also recently setup a systems biology project which aims at understanding the process of iron-sulfur cluster formation, in which frataxin is involved.||How muscles are assembled and regulated Understanding the molecular bases of muscle contraction has been one of the main research topics in biology for the last decades. Besides actin and myosin, which are the main players in muscle contraction, many other proteins have an essential role in determining muscle assembly and regulation. Several interactions have been described recently which are essential to anchor the muscle filaments to the modular proteins, such as titin, nebulin, and alpha-actinin. Dysfunctions in the interactions cause different types of cardio-myopathies and other muscle diseases. We are currently working to determine the structure of a number of protein complexes. This information will eventually allow us to reconstruct the muscle ultrastructure.


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Bonetti D (2014) The kinetics of folding of frataxin. in Physical chemistry chemical physics : PCCP

Description Newton Fellowship
Amount £96,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 11/2015 
End 10/2017
Description Understanding the aggregation properties of TDP43 in FTD
Amount £5,000,000 (GBP)
Organisation UK Dementia Research Institute 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 08/2021
Title Production of mylated peptides 
Description We developed a robust method to glycate peptides 
Type Of Material Biological samples 
Provided To Others? No  
Impact This allows the facile production of peptides with this post-translational modification 
Title Production of post-translational modification in proteins 
Description We designed a strategy to ubiquitinate ataxin-3 
Type Of Material Biological samples 
Year Produced 2013 
Provided To Others? Yes  
Impact We have provided a new methodology to produce suitable amounts of mono-ubiquitinated ataxin-3 
Title a new model for the causes of Friedreich's ataxia 
Description We identified the function of frataxin and provided a model for how its absence causes the disease 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2009 
Provided To Others? Yes  
Impact We provided information on how to mutate proteins for validating our model. 
Description Studies of misfolding diseases: polyQ and prion diseases 
Organisation French National Institute of Agricultural Research
Country France 
Sector Public 
PI Contribution NMR spectrometr time, know-how on NMR structural determination
Collaborator Contribution know-how on light scatterins, calorimetry and kinetics.
Impact Two publications in prreparation
Start Year 2008
Description Studies of the frataxin function 
Organisation Free University of Brussels
Country Belgium 
Sector Academic/University 
PI Contribution We have developed an assay which has allowed us to elucidate the function of frataxin
Collaborator Contribution co-authored publications and in vivo experiments to test our functional hypotheses
Impact As a result of this collaboration we are now part of an EU grant awarded for 2009-2012. Pandolfo, M., Pastore, A. (2008) The pathogenesis of Friedreich ataxia and the structure and function of frataxinJ. of Neurol. 256 Suppl 1:9-17
Start Year 2010
Description The mechanism of protein aggregation 
Organisation Moscow State University
Department Biochemistry Department
Country Russian Federation 
Sector Academic/University 
PI Contribution We have been collaborating on the effects of metals on the aggregation of the Abeta peptides.
Collaborator Contribution They produced the peptide and analysed the data collected in London
Impact We have been accepted a paper in Scientific reports.
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press release for our work on Friedreich's ataxia

The promotion of reserach on this disease. The establishment of a EU network to support the research further.
Year(s) Of Engagement Activity 2009
Description Publication of a science dissemination in Frontiers for young minds 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact I published an article in frontiers for Young Minds which is directed to children in the range of 8 to 16 years old. This initiative is meant to disseminate research among young people.
Year(s) Of Engagement Activity 2017