Stabilizing the Retromer Protein Complex with Molecular Chaperones For Alzheimer’s and Parkinson’s Diseases.
With our aging population comes an ever-increasing incidence of Alzheimer’s disease (AD), and other age-related dementias. By the year 2050, there is forecast to be more than 13 million people living with AD in the USA, and new treatments are desperately needed to prevent this impending epidemic. There are currently no effective therapies for AD, with current clinical trials all attempting to directly target amyloid beta (Aβ) peptides thought to be the driver of neuronal degeneration. In the long term, scientists believe that we may have to use cocktails of drugs to effectively slow the disease, much as we now do for diseases such as HIV/AIDS. A new concept in AD research is that cellular processes regulating protein turnover (ie, the balance between protein synthesis and protein degradation) could be manipulated to prevent the build-up of the toxic Aβ peptides that cause neurological failure. In this work, we will be developing novel small molecules and peptides that we hope will enhance this protein turnover in neurons, and provide a starting point for designing new AD drugs.
The major diseases of neurodegeneration and dementia are at their core caused by defects in protein homeostasis. This means that either an accumulation of toxic proteins and peptides is occurring, or the normal amounts of essential neuronal proteins are reduced. One of the pillars of neuronal regulation is the control of protein degradation and recycling within internal cellular compartments. This is essential for controlling the levels of synaptic receptors required for neurotransmission. It is also responsible for the removal of toxic cellular material causing neuronal degeneration, including the amyloid β (Aβ) peptide that causes Alzheimer’s disease (AD), α-synuclein involved in Parkinson’s (PD), and defective organelles such as damaged mitochondria. One of the most fundamental regulators of internal cellular trafficking is the retromer protein complex. Retromer subunits are down-regulated in the brain during the onset of sporadic late-onset AD, and familial mutations directly cause PD in subsets of patients. Conversely, its over-expression is neuroprotective in cell and animal disease models. Because of its central importance in these neurodegenerative disorders, retromer is attracting significant interest as a therapeutic target; and recent reports have confirmed that enhancing retromer activity using a small molecule chaperone can reverse both Aβ and α-synuclein accumulation in neuronal cell models. More generally, the processes of proteostasis and endolysosomal trafficking are emerging as highly attractive therapeutic targets in a number of neurodegenerative diseases.
This project will determine the mechanism of chaperone interaction with retromer and begin to identify new molecules with greater specificity and activity. The outcomes will be a better understanding of the molecular basis of retromer stabilization, providing a necessary platform for international medicinal chemistry efforts, and improved chaperone molecules that will provide both tools for further validation of retromer as a therapeutic target and leads towards the development of future drugs.
About the Researcher
Associate Professor Brett Collins is a lab head in the Institute for Molecular Bioscience at the University of Queensland in Australia, and currently holds a senior research fellowship from the Australian National Health and Medical Research Council (NHMRC). He did his PhD at Macquarie University in Sydney, studying the structures of RNA splicing factors, and then worked as a postdoctoral scientist at the Cambridge Institute for Medical Research, studying the molecular basis for the formation of clathrin-coated vesicles with Prof. David Owen. His lab studies now study the molecular mechanisms of membrane trafficking, with a focus on understanding how molecular interactions between proteins and lipids control this process. His approach is to combine protein structural information with biochemical and cellular studies to obtain molecular level insights into the interactions and functions of trafficking proteins involved in health and disease, including the sorting nexins and retromer complex which control endosomal membrane sorting and are defective in Alzheimer's and Parkinson's, and the regulation of SNARE-mediated membrane fusion in synaptic vesicle exocytosis.
My entry into the field of neuroscience has really been a slow process of gradual evolution. I began my adventures in structural biology attempting to use a technique called nuclear magnetic resonance spectroscopy (NMR) to study the molecular structures of small proteins called Sm/Lsm proteins involved in RNA splicing. This is where I first learned that, in science, things don't always work out the way you plan! I ended up instead studying these proteins using the method of X-ray crystallography, and have been a crystallographer ever since. I have always been fascinated by how their molecular forms dictate the way that proteins work in our cells -- from how they assemble, to how they interact with other proteins and biological molecules to control our physiology. After my PhD, I was fortunate to be mentored in a lab in Cambridge, working closely at the interface between structural biology and cell biology. This has given me a very strong appreciation for how multidisciplinary science can provide really significant insights into important cellular questions. In Cambridge, I mostly worked on proteins that modify the formation of clathrin-coated trafficking vesicles, and now I study distantly related protein complexes, such as "retromer" complexes that control how cellular organelles, called endosomes, regulate cellular homeostasis. This is where I have slowly been brought into the field of neurobiology, as these endosomal protein complexes are now known to be critical in various neurological diseases, including Alzheimer's and Parkinson's. This BrightFocus Grant will allow us to take some of the fundamental knowledge we have regarding the structure and function of these complexes and explore new avenues for targeting them in neurodegenerative disease.
First published on: July 18, 2018
Last modified on: July 19, 2018