Function of exosomes in neurodegenerative diseases

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Exosomes are 50-100 nm small vesicles which are secreted by a variety of cells. They can transfer genetic information, signalling proteins and pathogens such as HIV or prions between cells. Intercellular transmission of disease pathology has also been discussed in the context of neurodegenerative disorders. This was prompted by the finding that transplanted fetal neurons in Parkinson’s disease patients began to accumulate the intraneuronal alpha-synuclein aggregates that define the disease, indicating propagation of pathology from host to graft neurons. It is well established that aggregates of alpha-synuclein can act as seeds to trigger the aggregation of monomeric alpha-synuclein. Interneuronal transfer of alpha-synuclein oligomers could therefore induce aggregation in the host neuron and contribute to the dissemination of aggregates throughout the brain. We have shown that exosomes from neuronal cultures are enriched in oligomeric alphasynuclein. Therefore we propose that exosomes can act as “Trojan horses” in the transneuronal propagation of aggregates in neurodegenerative diseases. We will study the cellular machinery involved in targeting of aggregated proteins into exosomes, their release and internalisation by host neurons as well as exosome-mediated toxicity in host neurons. The in vivo relevance of exosomal disease propagation will be assessed by microinjection of synuclein containing exosomes derived from tissue culture, primary fibroblasts and cerebrospinal fluid of Parkinson’s disease patients into the brains of alpha-synuclein transgenic mouse models. We will monitor whether exosome injection can transmit the disease in mice and study the routes of interneuronal exosome spreading in transgenic mouse models.