Abstract
Nanoscopic aggregates of alpha-synuclein have been observed in Parkinson’s disease (PD). However, the processes that occur in-vivo leading to the formation of these small aggregates are not well understood. We used ultra-sensitive single-molecule methods including SIMOA and super-resolution microscopy to quantify and characterise alpha-synuclein aggregates harvested from human brain samples alongside the Line 61 mouse model using different tissue processing methods. While aggregate numbers did not differ between PD and control samples, larger aggregates were detected in PD brain samples. Moreover, different sub-populations of aggregates were obtained by different extraction methods, with diffusible and membrane-bound aggregates producing a more pronounced difference between disease and control samples. Our data suggests that alpha-synuclein aggregates slowly in the brain, leading to formation of larger aggregates in a sub-set of cells.
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Abstract
Nanoscopic aggregates of alpha-synuclein have been observed in Parkinson’s disease (PD). However, the processes that occur in-vivo leading to the formation of these small aggregates are not well understood. We used ultra-sensitive single-molecule methods including SIMOA and super-resolution microscopy to quantify and characterise alpha-synuclein aggregates harvested from human brain samples alongside the Line 61 mouse model using different tissue processing methods. While aggregate numbers did not differ between PD and control samples, larger aggregates were detected in PD brain samples. Moreover, different sub-populations of aggregates were obtained by different extraction methods, with diffusible and membrane-bound aggregates producing a more pronounced difference between disease and control samples. Our data suggests that alpha-synuclein aggregates slowly in the brain, leading to formation of larger aggregates in a sub-set of cells.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵# Co-first authors.
Conflict of interest: Authors declare no conflict of interest.
Some updates on data modelling and figures have been performed.
List of abbreviations
- □Syn
- Alpha synuclein
- aCSF
- Artificial cerebrospinal fluid
- DLB
- Dementia with Lewy body
- DNA-PAINT
- DNA Point Accumulation in Nanoscale Topography
- FRET
- Fluorescence energy transfer
- PD
- Parkinson’s disease
- Sarkosyl
- N-Laurylsacosine
- SIMOA
- Single-molecule array
- SiMPull
- Single-molecule pulldown
- SNARE
- Soluble N-ethylmaleimide-sensitive factor attachment protein receptor
- TBS
- Tris-buffered saline
- Thy1
- Thymocyte differentiation antigen 1
- TIRF
- Total internal reflection fluorescence
- TrX
- Triton X-100
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