Investigating the role of molecular chaperones in neurological diseases

Abstract

Most proteins are elaborate three-dimensional structures comprised of amino acids which form specific interactions with each other to bring about the structure of the protein. Thus, it is no surprise that mutating a single amino acid residue within a protein can completely alter its function or cause it to misfold and prematurely degrade. Given the importance of properly functioning proteins to carry out the daily functions within cells, it is important that these proteins are properly folded and ready to go. Chaperones are proteins that help fold other proteins or play a role in stabilizing them. Absence or mutation of chaperones can lead to devastating diseases or even lethality. TorsinA and NudC are two examples of critical chaperones that are implicated directly, or indirectly, in disease states. TorsinA is a protein that, when mutated, results in early-onset torsion dystonia. NudC on the other hand, plays a role in stabilizing Lis1, which is a causative protein agent of lissencephaly. In this collection of studies, we demonstrate that torsinA is a molecular chaperone capable of binding misfolded proteins directly and maintaining ER homeostasis through ATPase activity and proper ER localization. We also demonstrate that NudC chaperone activity is dependent on dimerization and that this function is conserved between NudC and the closely related NudCL homolog, but not the more distant homolog, NudCL2. Taken together, these studies suggest a possible mechanism for these proteins with respect to their chaperone function and stress the importance of understanding how chaperones function for advancing our understanding of disease.