Structural and Functional Insights into α-Synuclein Fibril Polymorphism.

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Abnormal alpha-synuclein (α-Syn) aggregation characterizes synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB).
• These diseases display clinical and pathological heterogeneity, mirroring prion disorders.
• Emerging evidence points to α-Syn self-assembly into conformationally distinct polymorphs, akin to prions.

Purpose of the Study:

• To review the clinical and pathological variability observed in synucleinopathies.
• To explore the phenomenon of alpha-synuclein (α-Syn) fibril polymorphism.
• To elucidate the structure-pathogenic relationship of α-Syn and its contribution to disease heterogeneity.

Main Methods:

• Review of existing literature on synucleinopathies, α-Syn aggregation, and prion-like behavior.
• Analysis of studies detailing α-Syn polymorphs, their structures, and in vivo/in vitro properties.
• Examination of research linking α-Syn strains to distinct pathological phenotypes in animal models.

Main Results:

• α-Syn can polymerize into conformationally diverse polymorphs, exhibiting strain-specific properties.
• These distinct α-Syn strains can induce different pathological phenotypes upon inoculation.
• High-resolution molecular structures and brain-derived α-Syn strains have been identified.

Conclusions:

• The conformational diversity of α-Syn aggregates (polymorphs) is a key factor in the heterogeneity of synucleinopathies.
• Understanding α-Syn polymorphism is crucial for deciphering the structure-pathogenic relationships in these neurodegenerative diseases.
• This knowledge advances our comprehension of clinical variability and may inform future therapeutic strategies for synucleinopathies.