Stabilising the retromer protein coplex with molecular chaperones for Alzheimer's and Parkinson's diseases
Many neurodegenerative diseases, including Alzheimer’s and Parkinson’s, are inherently disorders of protein homeostasis. Targeting of neuronal proteostasis for the treatment of neurodegenerative diseases and dementia is thus emerging as an area of significant interest for pharmaceutical development. But our understanding of these pathways, in neurons in particular, and our ability to pharmacologically manipulate these pathways is severely limited. One of the central mechanisms controlling neuronal proteostasis is the transport of proteins within the endolysosomal membrane controlled by a molecular machinery called the retromer complex. Retromer dysfunction has been strongly linked to neurodegenerative diseases, and such defects in cells and animal disease models can be rescued by the over-expression of retromer. Recent studies have confirmed that a retromer-enhancing small molecule chaperone can reverse both amyloid β and α-synuclein accumulation in neuronal cell models.
This project seeks to determine the molecular mechanism of chaperone interaction with retromer, and being to identify new molecules with greater specificity and activity. The implications will be a better understanding of the molecular basis of retromer stabilisation, providing a novel platform for the validation of retromer as a therapeutic target for neurodegenerative diseases and leads towards the development of future drug design.
Kevin Kai-En Chen is a postdoctoral research scientist at the Institute for Molecular Bioscience, The University of Queensland.