Alpha-Synuclein Aggregates Associated with Mitochondria in Tunnelling Nanotubes
Dario Valdinocci1, Jaromira Kovarova2, Jiri Neuzil1,2
1School of Medical Science, Griffith University, Gold Coast, Queensland, 4222, Australia.
Neurotoxicity Research
|September 14, 2020
Summary
Pathological alpha-synuclein (α-synuclein) aggregates associate with mitochondria within tunnelling nanotubes. This suggests mitochondria may facilitate the cell-to-cell spread of α-synuclein, contributing to Parkinson
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondrial interaction with alpha-synuclein (α-synuclein) is key in Parkinson's disease (PD) pathogenesis.
- The mechanism of pathological α-synuclein cell-to-cell spread in synucleinopathies remains largely unknown.
- Intercellular mitochondria transfer via tunnelling nanotubes (TNTs) is observed in other diseases but not yet in synucleinopathies.
Purpose of the Study:
- To investigate the role of tunnelling nanotubes (TNTs) in the intercellular transfer of pathological α-synuclein.
- To determine if α-synuclein interacts with mitochondria during intercellular transfer via TNTs.
Main Methods:
- Utilized co-culture and monoculture systems with 1321N1, THP-1, and SH-SY5Y cell lines.
- Employed super-resolution stimulated emission depletion (STED) microscopy to visualize α-synuclein and mitochondria.
- Performed siRNA knockdown of Miro1 to assess its role in mitochondrial association with α-synuclein in TNTs.
Main Results:
- Demonstrated direct interaction between α-synuclein and the mitochondrial outer membrane.
- Confirmed the presence of α-synuclein associated with mitochondria within TNTs connecting different cell types.
- Miro1 knockdown did not affect mitochondrial density or α-synuclein association with mitochondria in TNTs.
Conclusions:
- α-synuclein aggregates are associated with mitochondria within intercellular tunnelling nanotubes.
- Mitochondria-mediated transfer of α-synuclein via TNTs is a potential mechanism for disease propagation in synucleinopathies.
- This finding offers new insights into the cell-to-cell spread of Parkinson's disease pathology.
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