The interaction of α-synuclein with mitochondria in both typical and atypical Parkinson's disease is a critical component of degeneration. The mechanism of cell-to-cell propagation of pathological α-synuclein in synucleinopathies is unclear. Intercellular exchange of mitochondria along tunnelling nanotubes has been described in other diseases, such as cancer; however, its role in synucleinopathies is unknown. Pathological α-synuclein species have been demonstrated previously to move from cell to cell via tunnelling nanotubes. This process was further explored using co-culture and monoculture systems to determine if α-synuclein binds to migrating mitochondria within tunnelling nanotubes. Super-resolution analysis via stimulated emission depletion microscopy showed interaction between α-synuclein with the mitochondrial outer membrane and the presence of alpha-synuclein associated with mitochondria in tunnelling nanotubes between 1321N1, differentiated THP-1 and SH-SY5Y cell types. siRNA knockdown of Miro1, a critical protein-bridging mitochondria to the motor adaptor complex, had no effect on mitochondrial density or α-synuclein association with mitochondria in tunnelling nanotubes. The results show that α-synuclein aggregates associate with mitochondria in intercellular tunnelling nanotubes, suggesting that mitochondria-mediated α-synuclein transfer between cells may contribute to cell-to-cell spread of α-synuclein aggregates and disease propagation.

Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

School of Medical Science Griffith University Gold Coast Queensland 4222 Australia

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Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy