Exosome-mediated propagation of disease linked poly-dipeptides in C9orf72-FTD/ALS

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A growing body of evidence uncovered a propensity for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) pathogenic proteins to propagate from cell-to-cell. Although few other mechanisms have been proposed, secretion of exosomes has been reported to occur from different neural cell types, including neurons, and to potentially serve as a new intercellular communication route within the CNS. Interestingly, based on the evidence of focality and neuroanatomical propagation of clinical symptoms, it was also hypothesized that the cerebro-spinal fluid (CSF) could serve as vehicle for pathogenic proteins spread, at least in ALS. Utilizing different in vitro cell culture platforms, including spinal motor neurons derived from iPSCs of C9orf72 patients, we recently learnt that C9orf72-linked dipeptide proteins (DPRs) spread between neural cells via the exosome-dependent pathway. By analyzing a newly generated exosome-reporter transgenic mouse, we also found that exosomes are capable of migrating extensive distance in vivo. These observations led us to postulate that an exosome-mediated propagation of DPRs could be a modality by which toxic insults spread in disease-afflicted CNS areas in C9orf72-FTD/ALS. We will be testing using complementary in vitro and in vivo approaches the novel hypothesis that transmitted DPRs transfer injury via exosomes to both neighboring cells, but also to neurons downstream in synaptic circuits. We propose: (1) To investigate exosome-mediated mechanisms of DPRs transmission in CNS cells; (2) To examine the modalities of cell-to-cell propagation of DPRs in vivo; (3) To examine whether cell transfer of DPRs propagates toxicity. The proposed work has the potential to open up an entirely new field of C9orf72 FTD/ALS research, at the same time, providing important clues to the fundamental biological processes in brain cellular communications relevant to brain diseases. Thus, the results are expected to have a significant impact for understanding C9orf72-linked FTD/ALS pathogenesis and eventually treating patients.