Role for the alpha-helix in aberrant protein aggregation

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Tau protein is crucial for microtubule stability and implicated in Alzheimer's disease pathogenesis.
• Natively unfolded proteins, like tau, can adopt secondary structures under specific conditions.
• Aberrant protein aggregation is a hallmark of neurodegenerative diseases.

Purpose of the Study:

• To investigate if alpha-helix structures can induce the formation of abnormal protein aggregates.
• To explore the role of the helix-inducing agent TFE on tau protein aggregation in vitro.
• To characterize the structural properties and heterogeneity of tau aggregates.

Main Methods:

• In vitro aggregation assays of full-length tau protein using TFE as a helix-inducing agent.
• Spectroscopic analysis to determine alpha-helical content and aggregate structure.
• Dilution experiments to assess aggregate stability and heterogeneity.

Main Results:

• Full-length tau possesses residual alpha-helix structure, enhanced by disease-associated mutations.
• TFE induces morphologically and structurally heterogeneous aggregates in tau.
• Heterogeneity arises from competing alpha-helical fibrillar and amyloid-like aggregates.
• Alpha-helical aggregates exhibit coiled-coil features and are more dilution-resilient.

Conclusions:

• Intrinsically stable alpha-helices can self-associate into aggregates with coiled-coil symmetry.
• Tau protein's alpha-helix stability and coiled-coil symmetry may relate to its biological function.
• Alpha-helix formation is a potential trigger for aberrant protein aggregation in neurodegenerative diseases.