JPND: Altered mRNA translation as a pathogenic mechanism across neurodegenerative diseases

Lead Research Organisation: University of Cambridge
Department Name: Clinical Neurosciences

Abstract

Alterations in mRNA translation have been implicated in both neurodegenerative disorders, including Alzheimer's, prion, Parkinson's and Charcot-Marie-Tooth diseases, and neurodevelopmental diseases such as autism spectrum disorders. Currently, no curative treatments are available for these diseases, and the underlying molecular mechanisms are poorly understood, thus precluding rational drug design.
In this proposal, we aim to gain novel insights into the molecular pathogenesis of these diseases and to identify common and disparate mechanisms underlying the translation defects across diseases. The complexity of cellular and molecular mechanisms demands state-of-the-art methods. One such approach that we will use in our study is based on non-canonical amino acid tagging that will allow us to cell-type-specifically characterize translation in vivo and to identify genome-wide proteomic changes selectively in the affected neuronal populations in mouse models of the respective diseases. The functional relevance of identified molecular alterations for mRNA translation defects and disease phenotypes will be evaluated using cell, mouse and Drosophila models of disease.
By combining the complementary technical and thematic expertises of the consortium partners, we expect to gain unprecedented insights into the molecular mechanisms of these dreadful diseases and their associated translation defects, including insights into the cell type specific nature and late adult age of onset of neurodegenerative disorders. This may lay the foundation for rational drug design for these incurable diseases.

Technical Summary

Alterations in mRNA translation have been implicated in both neurodegenerative disorders, including Alzheimer's, prion, Parkinson's and Charcot-Marie-Tooth diseases, and neurodevelopmental diseases such as autism spectrum disorders. Currently, no curative treatments are available for these diseases, and the underlying molecular mechanisms are poorly understood, thus precluding rational drug design.
In this proposal, we aim to gain novel insights into the molecular pathogenesis of these diseases and to identify common and disparate mechanisms underlying the translation defects across diseases. The complexity of cellular and molecular mechanisms demands state-of-the-art methods. One such approach that we will use in our study is based on non-canonical amino acid tagging that will allow us to cell-type-specifically characterize translation in vivo and to identify genome-wide proteomic changes selectively in the affected neuronal populations in mouse models of the respective diseases. The functional relevance of identified molecular alterations for mRNA translation defects and disease phenotypes will be evaluated using cell, mouse and Drosophila models of disease.
By combining the complementary technical and thematic expertises of the consortium partners, we expect to gain unprecedented insights into the molecular mechanisms of these dreadful diseases and their associated translation defects, including insights into the cell type specific nature and late adult age of onset of neurodegenerative disorders. This may lay the foundation for rational drug design for these incurable diseases.

Planned Impact

This project is expected to identify - for the first time - the in vivo proteome of specific neuronal and glial populations in mice, and their alteration in disease models. Subsequent functional validation will allow to identify the changes that may causally contribute to disease. This, as well as hypothesis-driven approaches, mainly focusing on the eIF2alpha pathway, will allow us to identify common and disparate mechanisms underlying the translational defects across the investigated diseases (AD, PD, FTD, prion disease, ASD and CMT). In addition, we expect to gain novel insights into the cell type specific nature and late adult age of onset of neurodegenerative disorders. Finally, the fact that our validation studies will include patient-derived samples will greatly enhance the translational value of our project. Together, the added value of the network will allow us to identify and compare the underlying molecular mechanisms across diseases, which may lead to unprecedented novel insights into disease pathogenesis that may form the first step towards effective treatments for these incurable diseases.
We expect that the data resulting from the proposed experiments will give rise to several publications, most of which will be collaborative papers between two or more consortium partners or collaborators. As explained above under "project coordination and management", the network partners will keep each other up to date on recent scientific progress through monthly videoconferences and a yearly retreat with all people involved in the consortium. Furthermore, technical expertise will be shared through practical workshops for junior scientists and exchange of postdocs or PhD students between labs will be organized. This will allow optimal knowledge exchange. As indicated above and evident from the time table with allocation of work packages, numerous collaborations are planned which are mainly based on complementary expertises and access to biological material or high-end equipment.
We will disseminate the obtained results by publishing papers in scientific journals, presenting the work on scientific conferences, and press releases to inform the public. The largest amount of data will be generated by mass spectrometry (MS) and polysome profiling. Published datasets will be made available on publically accessible archives, such as ENA (European Nucleotide Archive, EBI), SRA (Sequence Reads Archive, NCBI), NCBI Peptidome and ProteomeXchange Consortium via the PRIDE partner repository (EBI).

Publications

10 25 50
 
Description Altered mRNA translation as a pathogenic mechanism across ND 
Organisation Max Planck Society
Department Max Planck Institute for Brain Research
Country Germany 
Sector Academic/University 
PI Contribution Expertise in the field of neurodegeneration and the unfolded protein response
Collaborator Contribution Expertise in mRNA translation and neurodegenerative diseases
Impact None so far
Start Year 2018
 
Description Altered mRNA translation as a pathogenic mechanism across ND 
Organisation Max Planck Society
Department Max Planck Institute for Molecular Biomedicine
Country Germany 
Sector Academic/University 
PI Contribution Expertise in the field of neurodegeneration and the unfolded protein response
Collaborator Contribution Expertise in mRNA translation and neurodegenerative diseases
Impact None so far
Start Year 2018
 
Description Altered mRNA translation as a pathogenic mechanism across ND 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution Expertise in the field of neurodegeneration and the unfolded protein response
Collaborator Contribution Expertise in mRNA translation and neurodegenerative diseases
Impact None so far
Start Year 2018
 
Description Altered mRNA translation as a pathogenic mechanism across ND 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Academic/University 
PI Contribution Expertise in the field of neurodegeneration and the unfolded protein response
Collaborator Contribution Expertise in mRNA translation and neurodegenerative diseases
Impact None so far
Start Year 2018
 
Description Alzheimer's Research UK - Staff Away Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Supporters
Results and Impact Talk at the Alzheimer's Research UK annual staff away day. Raising awareness about the activities of the Cambridge DRI.
Year(s) Of Engagement Activity 2019
 
Description Glioma/Translation/Metabolism Workshop, Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Glioma/translation/metabolism grant workshop at Glasgow University
Year(s) Of Engagement Activity 2019
 
Description Isle of Man Dementia Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Talk on the potential use of Trazadone in preventing the formation of tau tangles at the Isle of Man Dementia Conference - Alzheimer's Society.
Year(s) Of Engagement Activity 2019
 
Description Neurodegenerative Diseases: Biology & Therapeutics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A primary goal of the meeting is to provide a forum where medical scientists from academia can interact with scientists from the biopharmaceutical industry, thus forging a community of academic and industry researchers who recognize that they have much to learn from each other. Rational drug discovery for neurodegenerative diseases has begun to yield compounds and treatments that are now entering clinical settings. For human studies utilizing these compounds and treatments to be maximally informative, it is crucial that scientists from academia and industry meet regularly to exchange data and ideas.

Professor Mallucci delivered a talk on: UPR activation in astrocytes induces non-cell autonomous neurotoxicity in neurodegenerative disease.
Year(s) Of Engagement Activity 2018
URL https://meetings.cshl.edu/meetings.aspx?meet=DEGEN&year=18
 
Description RESEARCH WORKSHOP OF THE ISRAEL SCIENCE FOUNDATION AND THE MIZRACHI FOUNDATION 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professional Practitioners workshop to discuss and debate the regulation of mRNA translation by miRNA, proteostasis, or epigenetics and its role in learning and memory and synaptic plasticity in normal and abnormal brain function. Professor Mallucci delivered her talk on The role of non-cell autonomous regulation of protein synthesis rates in neurodegenerative disease, which was then discussed and debated.
Year(s) Of Engagement Activity 2018
URL http://neurosenblum.haifa.ac.il/index.php/meetings
 
Description SONA Webinars 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Society of Neuroscientists of Africa SONA WEBINAR SERIES
Title: Mechanisms to Medicines in Neurodegeneration
Speaker: Prof. Giovanna Mallucci
Associate Director of the UK Dementia Research Institute
University of Cambridge, UK
Year(s) Of Engagement Activity 2019
URL https://www.youtube.com/watch?v=n0-OCVPP6EE