Super-resolution imaging reveals α-synuclein seeded aggregation in SH-SY5Y cells

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alpha-synuclein (α-syn) aggregation is a hallmark of Parkinson's disease (PD) and related synucleinopathies.
• The mechanism of α-syn aggregate propagation in the brain remains largely unknown.
• Understanding cellular uptake and seeding efficiencies is crucial for elucidating propagation mechanisms.

Purpose of the Study:

• To quantitatively assess the cellular uptake and seeding efficiency of exogenous α-syn fibrils.
• To investigate the cellular response to α-syn seeding, including aggregate formation and secretion.
• To explore the role of the proteasome in the α-syn seeding process.

Main Methods:

• Super-resolution microscopy was employed to image the uptake and seeding of unlabeled α-syn fibrils by SH-SY5Y cells.
• Quantitative analysis of intracellular and secreted α-syn aggregates was performed.
• The influence of proteasome activity on the seeding process was examined.

Main Results:

• Exogenous α-syn fibrils showed inefficient induction of endogenous α-syn self-assembly.
• Proteasome activity accelerated the seeding process.
• Cells responded to seeding by secreting nanoscopic aggregates (mean 35 nm diameter) containing both α-syn and Aβ.

Conclusions:

• Cellular uptake of α-syn seeds is inefficient, but seeding can disrupt protein homeostasis.
• Cells predominantly respond to seed-induced disruption by secreting nanoscopic aggregates.
• This secretion of nanoscopic aggregates may represent a cellular protective mechanism against protein aggregation.