Understanding the balance between functional and deleterious interactions of alpha-synuclein with lipid bilayers

Project Information

toxiclipasyn

Grant agreement ID: 706551

DOI

10.3030/706551

Project terminated on 31 March 2019

EC signature date 8 November 2016

Start date 1 May 2017

End date 30 April 2019

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 171 460,80

EU contribution

€ 171 460,80

Coordinated by

DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Germany

Periodic Reporting for period 1 - toxiclipasyn (Understanding the balance between functional and deleterious interactions of alpha-synuclein with lipid bilayers)

Reporting period: 2017-05-01 to 2019-04-30

Summary of the context and overall objectives of the project

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder at older age causing disability and care dependency. In 2016, more than six million people were diagnosed with PD and this number is expected to increase by 92% over the next 40 years. Such an increase in the number of patients will lead to significant social and financial burden on our ageing societies.

PD is characterized by the deposition of protein clumps called Lewy Bodies (LB) and Lewy neurites (LN) in the brain of patients. LB and LN are mainly composed of the protein alpha-synuclein but can also contain lipid (fat) molecules, the main constituents of biological membrane. A-synuclein interacts with membranes as part of its functional role, i.e. to help neurons to communicate with one another, but alpha-synuclein also form clumps in their presence. Indeed, the nature of lipids in membrane dictates whether or not alpha-synuclein is functional or can form clumps.

This action aimed at identifying changes in lipid levels and/ or properties associated with PD and determining their influence on the propensity of alpha-synuclein to form clumps.

The aims of this action were overall successfully addressed.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the course of this action, biological membranes were isolated from different animal and cellular models of PD. Their lipid composition was determined and the extent to which they were able to initiate the formation of clumps by alpha-synuclein was investigated.

The results of this action allowed the identification of a list of lipids whose levels and properties affect alpha-synuclein aggregation under pathophysiologically relevant conditions. In particular, data support the concept that PD risk factors may act by changing cellular lipid profiles and thus promoting the formation of alpha-synuclein clumps.

These results are currently described in a manuscript in preparation for publication. Once published, these results will be presented in conferences targeted at scientists in the field of neuroscience, lipid metabolism and protein aggregation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The results provide new insights into the role of lipids in the pathogenesis of PD and support a role of lipid-alpha-synuclein interactions as a mechanism of increased PD risk. They also have the potential to help the development of new diagnostic tools and pharmaceutical treatments.

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