Late-onset Alzheimer’s disease (LOAD) is a prevalent form of dementia that typically manifests after the age of 65. Individuals carrying clusterin risk alleles are at a higher risk of developing LOAD, making the clusterin protein a focal point for researchers. A recent study conducted by researchers at the Max Planck Institute of Biochemistry has delved into the molecular underpinnings of clusterin’s chaperone function to gain a deeper understanding of its role.
The groundbreaking research led by Patricia Yuste-Checa, Andreas Bracher, and F.-Ulrich Hartl, Director and Head of the Department of Cellular Biochemistry, utilized X-ray crystallography to unveil the three-dimensional crystal structure of human clusterin for the first time. This structural insight sheds light on the protein’s chaperone function and mode of action.
The study revealed that clusterin comprises three distinct domains, with a particular focus on two disordered, hydrophobic peptide tails that endow the protein with its versatile nature. Yuste-Checa elucidates, “The structure of the peptide tails resembles that of small heat shock proteins, which act as molecular chaperones inside cells to prevent protein aggregation. Clusterin, however, operates outside of cells.”
Proper protein folding is crucial for their functionality within cells, as misfolding can lead to the formation of harmful aggregates associated with neurodegenerative diseases like Alzheimer’s and Parkinson’s. Molecular chaperones such as clusterin play a pivotal role in preventing this misfolding process. Despite being identified as a secreted glycoprotein in the 1980s, the molecular mechanisms of clusterin’s protective functions have remained poorly understood until now.
Clusterin’s extracellular role involves binding to misfolded proteins, including amyloid beta, tau, and α-synuclein, which are hallmark features of neurodegenerative diseases, and halting their further aggregation. The study highlighted the indispensable role of the hydrophobic peptide tails in clusterin’s protective function. Modification or removal of these amino acids resulted in the loss of chaperone activity against amyloid beta aggregation, emphasizing the significance of these tails in mediating clusterin’s functions.
The newfound insights into clusterin’s structure and function hold significant medical implications. Andreas Bracher notes, “Clusterin exhibits a myriad of functions, ranging from cell aggregation and apolipoprotein activity to complement system inhibition, molecular chaperoning, and anti-apoptotic properties.” Understanding the intricacies of clusterin’s structure and mechanism provides novel perspectives on extracellular protein stability control, offering potential avenues for clinical research and future therapeutic interventions for neurodegenerative diseases.
In conclusion, the elucidation of the molecular basis for clusterin’s chaperone function represents a crucial step towards unraveling the complexities of neurodegenerative diseases. The study’s findings pave the way for further exploration of clusterin’s therapeutic potential and its implications in the treatment of Alzheimer’s and other related conditions.
