NEUROTUNN · Mechanisms of α-synuclein spreading, implications for synucleinopathies
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-03-01 → 2018-02-28
- EU contribution
- €185,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Mechanisms of α-synuclein spreading, implications for synucleinopathies
Parkinson’s Disease (PD) is a major health problem particularly for European aging populations. Since the etiology of PD remains unknown and an effective therapeutic intervention is not yet available, the recent observations that prion-like mechanisms underlie the pathological spreading of misfolded α-synuclein (α-syn) and other proteins represent a ground-breaking discovery with extensive implications. PD is a neurodegenerative disorder related to aging, characterized by intracellular deposits of aggregated α-synuclein (α-syn) known as Lewy bodies and Lewy neurites. In PD patients, at late stages of disease, deposits of α-syn aggregates are widely spread in the central nervous system (CNS). Several studies have shown that Lewy bodies may propagate within the brain in a prion-like manner, which means that the disease may be transmissible by self-propagation of the protein misfolding process in a similar way as prions transmit prion diseases. However, the exact underlying route(s) allowing the physical movement of the protein aggregates from one cell to another and the cellular players involved in this process are not yet fully understood. Thus, considerable amount of research has focused in clarifying this possibility with the aim of translating the knowledge of the basic disease mechanisms into development of novel strategies for early diagnosis and efficient treatment. Accordingly, by using novel systems of primary cultures combined with state-of-the-art imaging approaches, the general aims of the project were to 1) unveil the mechanisms of propagation of α-syn protein assemblies, 2) assess the possible involvement of tunneling nanotubes (TNTs), which are thin actin-rich membrane bridges that allow exchange of cellular components between cells, in the transfer process and, 3) evaluate if non-cell autonomous processes, namely neuron-glial interactions, contribute to either clearance or dissemination of α-syn aggregated species between the CNS cells. In summary, this project addresses three open questions in the field; the unequivocal identification of the mechanism of α-syn transfer in neurons, the possible involvement of TNTs in α-syn transfer and the impact of glial cells to the pathology. Providing answers to these and other related research questions is of paramount importance mainly from a therapeutic point of view.
Data: CORDIS, © European Union
Project objective
A common feature of neurodegenerative diseases, including highly prevalent illnesses, is the presence of misfolded protein aggregates in affected regions of the nervous system. Aggregates result from the misfolding of one or more specific proteins, for example, amyloid-β in Alzheimer’s disease, α-synuclein in Parkinson’s disease, and the normal prion protein in transmissible spongiform encephalopathies (TSEs). Recently a series of exciting studies has suggested a prion-like mechanism underlying the pathological spreading of misfolded proteins (mainly tau, α-synuclein and huntingtin) involved in various neurodegenerative diseases. Particularly striking is the recovery of α-synuclein aggregates from engrafted embryonic neurons in post-mortem brains transplanted from Parkinson’s patients. Thus, while questioning the therapeutic use of transplants, the understanding of the molecular and cellular fundaments of cell-to-cell transmission of proteinaceous aggregates is clearly in the early stages of investigation and may represent a more readily accessible target for novel disease-modifying therapies, allowing the development of possible common therapeutic strategies. Tunneling nanotubes (TNTs) represent a novel mechanism of direct intercellular communication that has been shown to mediate both transfer of prions between neuronal cells and the passage of poliQ huntingtin between neurons. We hypothesize that TNT-mediated transfer of amyloidogenic protein aggregates represents one of the main pathways of communication between cells. Thus, molecules involved in TNT formation could represent valuable targets for the disease prevention. Here I will assess the underlying mechanism of cell-to cell transfer of α-synuclein, exploring whether its transport could be mediated by TNTs in physiologically relevant in vitro models, evaluating as well the possible contribution of non-cell autonomous processes, via neuron-glial interactions, to the pathological spreading of the protein.
Original text from CORDIS.
Participants
- INSTITUT PASTEUR · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union