Lipid Acyl Chain-Driven α-Synuclein Fibril Polymorphisms and Neuronal Pathologies.

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alpha-synuclein (α-syn) fibril conformations are linked to distinct synucleinopathy phenotypes like Parkinson's disease (PD).
• Membranes are increasingly recognized as crucial factors influencing α-syn fibril structure.
• The impact of age-related membrane changes on α-syn fibril formation and disease remains largely unexplored.

Purpose of the Study:

• To investigate how age-related alterations in neuronal membrane composition and fluidity affect α-syn fibril formation.
• To determine the influence of these membrane changes on fibril pathogenicity and cellular outcomes.

Main Methods:

• Utilized complex membrane mixtures mimicking normal and age-altered neuronal membranes.
• Grew α-syn fibrils in the presence of these membranes and analyzed structural differences using 2D ssNMR.
• Assessed fibril-membrane association and their impact on neuronal pathologies.

Main Results:

• α-syn fibrils grown with age-related membranes showed distinct structural patterns compared to lipid-free fibrils.
• Fibrils associated with age-related membranes exhibited weaker binding than those with normal membranes.
• Membrane-associated fibrils induced more severe neuronal pathologies, with variations in aggregation and inflammation.

Conclusions:

• Age-related membrane changes significantly shape α-syn fibril structure and pathogenicity.
• This study highlights the critical role of membrane dynamics in amyloid-driven neurodegeneration.
• Findings provide novel insights into the molecular mechanisms underlying synucleinopathies.