Stochastic Optical Reconstruction Microscopy Imaging of Multiple System Atrophy Inclusions Suggests Stepwise α-Synuclein Aggregation
Benoît Vovard1,2, Alexia Bodin1,2, Julien Gouju2,3
1Univ Angers, Equipe MitoLab, Unité MitoVasc, Inserm U1083, CNRS 6015, SFR ICAT, Angers, France.
Background:
The architecture and composition of glial (GCI) and neuronal (NCI) α-synuclein inclusions observed in multiple system atrophy (MSA) remain to be precisely defined to better understand the disease.
Methods:
Here, we used stochastic optical reconstruction microscopy (STORM) to characterize the nanoscale organization of glial (GCI) and neuronal (NCI) α-synuclein inclusions in cryopreserved brain sections from MSA patients.
Results:
STORM revealed a dense cross-linked internal structure of α-synuclein in all GCI and NCI. The internal architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells, suggesting a common aggregation mechanism. A similar sequence of p-αSyn stepwise intracellular aggregation was defined in oligodendrocytes and neurons, starting from the perinuclear area and growing inside the cells. Consistent with this hypothesis, we found a higher mitochondrial density in GCI and NCI compared to oligodendrocytes and neurons from unaffected donors (P < 0.01), suggesting an active recruitment of the organelles during the aggregation process.
Conclusions:
These first STORM images of GCI and NCI suggest stepwise α-synuclein aggregation in MSA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Insights
This study used STORM microscopy to investigate α-synuclein inclusions in multiple system atrophy (MSA). Findings reveal a stepwise aggregation process in both glial (GCI) and neuronal (NCI) cells, suggesting a common mechanism.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Multiple system atrophy (MSA) is characterized by glial (GCI) and neuronal (NCI) α-synuclein inclusions.
- The precise architecture and composition of these inclusions are not well understood.
- Understanding these inclusions is crucial for deciphering MSA pathogenesis.
Purpose of the Study:
- To characterize the nanoscale organization of α-synuclein inclusions in MSA.
- To investigate the potential common aggregation mechanisms in glial and neuronal cells.
Main Methods:
- Stochastic optical reconstruction microscopy (STORM) was employed.
- Cryopreserved brain sections from MSA patients were analyzed.
- Nanoscale organization of GCI and NCI was examined.
Main Results:
- STORM imaging revealed a dense, cross-linked internal structure of α-synuclein in all GCI and NCI.
- The architecture of hyperphosphorylated α-synuclein (p-αSyn) inclusions was similar in glial and neuronal cells.
- A common stepwise intracellular aggregation sequence, starting from the perinuclear area, was observed in both cell types.
- Higher mitochondrial density was noted in GCI and NCI compared to unaffected cells, suggesting organelle recruitment.
Conclusions:
- These findings provide the first STORM images of GCI and NCI in MSA.
- The results suggest a stepwise α-synuclein aggregation process common to both glial and neuronal cells in MSA.
- This sheds light on the aggregation mechanisms underlying MSA pathology.
