Trehalose-Induced Structural Transition Accelerates Aggregation of α-Synuclein

Area of Science:

• Biochemistry
• Protein Misfolding Diseases
• Neurodegenerative Disorders

Background:

• Alpha-synuclein (α-synuclein) fibrillation is central to Parkinson's disease pathogenesis.
• Protein aggregation is a hallmark of many neurodegenerative conditions.
• Osmolytes are known to stabilize proteins and inhibit aggregation.

Purpose of the Study:

• To investigate the effect of the osmolyte trehalose on α-synuclein fibrillation.
• To understand how trehalose influences the aggregation pathway of intrinsically disordered proteins.
• To compare trehalose's effect on intrinsically disordered proteins versus natively folded proteins.

Main Methods:

• Studied the fibrillation process of α-synuclein.
• Investigated the conformational changes induced by trehalose.
• Analyzed the impact of trehalose on protein folding pathways and aggregation intermediates.

Main Results:

• Trehalose, a stabilizer, was found to order α-synuclein into a non-native conformation.
• This ordering effect drives the protein folding pathway towards aggregation.
• The osmolyte trehalose exhibited a variable effect on the intrinsically disordered α-synuclein compared to natively folded proteins.

Conclusions:

• Trehalose can promote aggregation of intrinsically disordered proteins like α-synuclein.
• The mechanism involves ordering of pathway intermediates, not simple stabilization.
• This finding has implications for understanding and potentially treating diseases involving protein aggregation.