Targeting exosome-mediated propagation of protein misfolding in MND

MND is characterised by anatomically focal onset of symptoms which radiate in a contiguous pattern, consistent with propagation of underlying motor neuron loss and pathology.

The factor(s) that mediate neuroanatomical spread of MND remain debated, but these are likely to be diffusible, present in extracellular fluids and therefore targetable. We recently discovered that intercellular propagation of protein misfolding is mediated by "exosomes" in MND models.

Aims

This project seeks to modulate exosome secretion in human primary motor neuron culture systems and transgenic mouse models of MND

The effects of genetic and chemical approaches to modulate exosome release will be evaluated on clinical progression, neuropathology and distribution of misfolded proteins in the central nervous system of mouse models of MND.

Exosomes are small secretory vesicles released by cells and capable of transmitting RNA and protein to recipient cells. This project seeks to modulate exosome secretion in human primary motor neuron culture systems and transgenic mouse models of MND. The effects of genetic and chemical approaches to modulate exosome release will be evaluated on clinical progression, neuropathology and distribution of misfolded proteins in the central nervous system of mouse models of MND.

Electron micrograph of exosomes secreted by motor neuronal cells and stained for misfolded SOD1 protein

Key paper

Grad LI,* Yerbury JJ,* Turner BJ*, Guest WC, Pokrishevsky E, O'Neill MA, Yanai A, Silverman JM, Zeineddine R, Corcoran L, Kumita JR, Luheshi LM, Yousefi M, Coleman BM, Hill AF, Plotkin SS, Mackenzie IR, Cashman NR (2014) Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc Natl Acad Sci USA 111:3620-3625. *equal first author.

http://www.ncbi.nlm.nih.gov/pubmed/24550511