Alpha-Synuclein Aggregates Associated with Mitochondria in Tunnelling Nanotubes

The interaction of alpha-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 alpha-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 alpha-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 alpha-synuclein binds to migrating mitochondria within tunnelling nanotubes. Super-resolution analysis via stimulated emission depletion microscopy showed interaction between alpha-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 alpha-synuclein association with mitochondria in tunnelling nanotubes. The results show that alpha-synuclein aggregates associate with mitochondria in intercellular tunnelling nanotubes, suggesting that mitochondria-mediated alpha-synuclein transfer between cells may contribute to cell-to-cell spread of alpha-synuclein aggregates and disease propagation.

Automated summary

The interaction of pathological alpha-synuclein with mitochondria through tunneling nanotubes in synucleinopathies may contribute to the cell-to-cell spread of aggregates, potentially leading to disease propagation.