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Mechanisms of α-synuclein spreading, implications for synucleinopathies

Mechanisms of α-synuclein spreading, implications for synucleinopathies

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.

Coordinator

INSTITUT PASTEUR

Address

Rue Du Docteur Roux 25-28
75724 Paris Cedex 15

France

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 185 076

Project information

Grant agreement ID: 702465

  • Start date

    1 March 2016

  • End date

    28 February 2018

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 185 076

  • EU contribution

    € 185 076

Coordinated by:

INSTITUT PASTEUR

France