The role of Park 6 gene in Parkinson's Disease.

Lead Research Organisation: University College London
Department Name: UNLISTED

Abstract

Part of this preliminary work was funded by the Parkinson s disease society. This lay society has over 20000 members. We have spoken to the officers of the society and we would seek to communicate the rsearch findings to their membership in a form that is accessible.
UCL and UCLH trust is developing a forum for genetics in society. This initiative includes ethicists, social scientists, computer researchers as well as geneticists. One of its chief aims is to evaluate and develop protocols for dissemination of the results of genetic studies to the public as well as facilitating translation into clinical practice. The lead applicant is a key member of this initiative.
The communication of genetic results to families is clearly of great importance. Where appropriate it is the practice in this institution to communicate any relevant results to families through the neurogenetic clinic of the national Hospital. this clinic is run by the lead applicant.

Technical Summary

We previously identified a novel autosomal recessive Parkinson‘s disease (PD) locus on chromosome 1p36 (PARK6). We have very recently shown that mutations in PINK1, a protein kinase which co-localizes to the mitochondria, are causal in PARK6. We identified missense and nonsense mutations in consanguineous European families. Subsequent sequencing of sporadic PD patients revealed a further five separate missense mutations affecting highly conserved amino acids of the kinase domain and a nonsense mutation which truncates the C-terminal regulatory region of the protein, indicating that mutations of this gene are a significant cause of PD.
For the first time we implicate a protein kinase in PD, a finding which will have important ramifications to the study of the aetio-pathogenesis of a disease which hitherto has been considered to be primarily a protein handling disorder.
Preliminary work on the function of the protein shows that PINK1 localizes to the mitochondria, and that one of the familial missense mutations affects mitochondrial membrane potential. Furthermore, we have demonstrated direct interaction with the oncoprotein PKC and synphilin-1 (SNCAIP.) An in silico model of the protein predicts that all eight mutations would affect either kinase activity, regulation or substrate recognition.
We have therefore placed PINK1 within the well characterised PKC signal transduction pathway and show that mutations in the gene could affect cell viability through disruption of mitochondrial integrity. Further work is now required to elucidate the upstream regulators of kinase activity. Characterisation of the kinase will facilitate identification of its downstream targets and hence the effects of the mutations on these targets. Using cellular models we will address the wider issues of the effects of the mutations on protein interactions, subcellular localisation and cell viability under stress. Creation of a mouse knockout/knockin model will allow detailed in vivo analysis of the cellular as well as pathological effects of the mutations.

Publications

10 25 50
 
Description 2008 - NIHR - Senior Investigator - nwood
Amount £45,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2008 
End 03/2019
 
Description 2009 - NIHR - UCL/UCLH Comprehensive Biomedical Centre Capital Project - nwood
Amount £466,500 (GBP)
Organisation National Institute for Health Research 
Department UCLH/UCL Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 12/2009 
End 07/2011
 
Description 2009 - PUK - Project Grant - nwood
Amount £292,590 (GBP)
Funding ID J-0804 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2009 
End 10/2011
 
Description 2010 - MJFF - Investigating Signaling Pathway Dysfunction Linked to LRRK2 - plewis
Amount £357,022 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2010 
End 12/2011
 
Description 2010 - MRC - Senior Fellowship
Amount £1,543,359 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description 2010 - WT/MRC - Wellcome Trust Strategic Award: A systematic investigation into the pathogenesis and course of Parkinson's syndrome - nwood
Amount £5,952,982 (GBP)
Funding ID 089698 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2010 
End 12/2015
 
Description 2011 - AMS - Starter Grants for Clinical Lecturers - sgandhi
Amount £30,000 (GBP)
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2013
 
Description 2011 - PUK - PhD Studentship
Amount £90,580 (GBP)
Funding ID H-1006 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2011 
End 01/2014
 
Description Parkinson's disease society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact A brief lecture on outputs from research

Nil
Year(s) Of Engagement Activity 2009
 
Description Public engagement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact My research group hosted and presented to a group of >20 visiting American university students with a focus on translational medicine: from bench to bedside. The main focus was on diverse aspect of cardiovascular research from fundamental research to clinical applications. This was followed by question/answer session. The general feedback from the organisers and students was very positive. Organisers comments included "great learning opportunity for our students!" "The students not only learned about your specific research area, but could relate translational medicine concepts taught in class to real-life scientific scenarios presented by you and your students. " Students comments included: "? It was refreshing to hear different speakers of different levels on the same topic because it gave different perspectives.
? Very in depth presentation. Gave a well-rounded view of pre-clinical research.
? I really like how the speaker had three phd students talked about 3 different research focus to a common target (Pou4/Brn3). I think it was a very comprehensive way to look at the target and better understand what they are working with. Very informative and easy to understand.
We subsequently received requests for additional visit from different participants.
Year(s) Of Engagement Activity 2017,2018
 
Description School visit (Haberdashers Aske Boys School) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Raising awareness of scientific research and impact on society. Engaging with students who are interested in undertaking studies in biological sciences at a higher level.
Year(s) Of Engagement Activity 2016,2017
 
Description UCL cardiovascular symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Reporting progress on research undertaken in the cardiovascular and links to metabolic studies.
Year(s) Of Engagement Activity 2017
 
Description Work experience opportunities to enhance engagement in higher education and research in STEM subjects 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Provided the opportunity for young students (>16 years) to participate in supervised research activities in a laboratory setting. This involved providing secure environment and supervision for GCSE, A-level or undergraduate students to be involved in laboratory research.
This has provide tremendous interest and resulted in request to host other students from multiple schools as well as to participate in open career evenings.
Year(s) Of Engagement Activity 2016,2017,2018,2019