Annular alpha-synuclein species from purified multiple system atrophy inclusions

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Multiple system atrophy (MSA) is characterized by alpha-synuclein aggregates in oligodendroglial inclusions.
• Increased high-molecular-weight, detergent-resistant alpha-synuclein species are found in MSA cortical tissue.

Purpose of the Study:

• To analyze the ultrastructure of alpha-synuclein aggregates from pathological MSA samples.
• To investigate the morphology of alpha-synuclein species released from pathological aggregates by detergents.

Main Methods:

• Immunopurification of alpha-synuclein aggregates from MSA cortical tissue.
• Ultrastructural analysis using scanning electron microscopy (SEM) and atomic force microscopy (AFM).
• Detergent treatment (sarcosine, CHAPS) of pathological and recombinant alpha-synuclein, followed by morphological characterization.

Main Results:

• Purified pathological aggregates consisted of filament bundles.
• Detergent treatment of pathological aggregates released 30-50 nm annular alpha-synuclein particles.
• Detergent treatment of recombinant alpha-synuclein produced only 10-18 nm spherical particles.
• Annular structures were confirmed to be positive for alpha-synuclein.

Conclusions:

• Pathological alpha-synuclein from MSA forms distinct annular structures upon detergent treatment, differing from recombinant alpha-synuclein.
• The formation of these annular aggregates may contribute to alpha-synuclein toxicity in MSA.
• These findings may inform the development of therapeutic strategies targeting alpha-synuclein aggregates.