Alpha-Synuclein Aggregates Associated with Mitochondria in Tunnelling Nanotubes
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ORIGINAL ARTICLE
Alpha-Synuclein Aggregates Associated with Mitochondria in Tunnelling Nanotubes Dario Valdinocci 1 & Jaromira Kovarova 2 & Jiri Neuzil 1,2 & Dean L. Pountney 1 Received: 29 June 2020 / Revised: 31 August 2020 / Accepted: 2 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 αsynuclein 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. Keywords Alpha-synuclein . Parkinson’s disease . Tunnelling nanotube . Mitochondria . Miro1
Abbreviations CNS Central nervous system dH2O Deionised H2O DMEM Dulbecco’s modified Eagle medium FACS Fluorescence-activated cell sorting MSA Multiple system atrophy NGS Normal goat serum NHS Normal Horse serum PBS Phosphate-buffered saline PD Parkinson’s disease PMA Phorbol-12-myristate-13-acetate RIPA Radioimmunoprecipitation assay ROS Reactive oxygen species RT Room temperature
* Dean L. Pountney [email protected] 1
School of Medical Science, Griffith University, Gold Coast, Queensland 4222, Australia
2
Institute of Biotechnology (BIOCEV), Czech Academy of Sciences, Prague-West, Czech Republic
SDS siRNA STED TnTs TOM WB
Sodium dodecyl sulfate Silencer RNA Stimulated emission depletion Tunnelling nanotubes Translocase of outer membrane receptor Western blot
Introduction Interaction of α-synuclein (α-syn) protein aggregates with mitochondria is a critical component of degeneration in both typical and atypical Parkinson’s disease (PD) (Valdinocci et al. 2019). Previous studies have linked the progression of PD to the transmission of α-syn aggregates from cell-to-cell, thereby mediating the spread of disease pathology to adjacent neuro
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