Function within Disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation

Area of Science:

• Neurobiology
• Molecular Biology
• Protein Biochemistry

Background:

• Tau aggregation is a hallmark of neurodegenerative tauopathies.
• Small heat shock proteins (sHSPs) are crucial for protein homeostasis and preventing aggregation.
• HSPB1 (Hsp27) and HSPB5 (αB-crystallin) are brain-expressed sHSPs that interact with tau.

Purpose of the Study:

• To elucidate the distinct mechanisms by which HSPB1 and HSPB5 inhibit tau aggregation.
• To identify the specific regions within sHSPs responsible for their anti-aggregation activity.
• To understand how cellular stress and post-translational modifications regulate sHSP function in tauopathies.

Main Methods:

• In vitro assays to monitor tau aggregation.
• Construction and testing of chimeric HSPB1/HSPB5 proteins with swapped N-terminal regions.
• Analysis of functional regions within the disordered N-terminal domains (NTRs).

Main Results:

• HSPB1 and HSPB5 delay tau aggregation via distinct mechanisms controlled by their NTRs.
• HSPB1 inhibits tau aggregation under normal conditions; HSPB5 requires stress activation (e.g., acidosis).
• Specific functional motifs within the NTRs modulate chaperone activity and client engagement.

Conclusions:

• Disordered N-terminal regions of sHSPs contain critical functional motifs for tau aggregation inhibition.
• sHSP activity is finely tuned by cellular stress and post-translational modifications like phosphorylation.
• These findings offer insights into therapeutic strategies targeting sHSPs for tauopathies.