Grant: Operating Grant

Neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, are the leading causes of disability in Canada. These devastating conditions are caused by the progressive loss of function of brain cells called neurons. As this pathological phenomenon is strongly linked to the buildup of damaging protein masses in neurons, one potential treatment is to activate the neuronal cells' internal machineries to remove these toxic protein masses. Autophagy is a pathway used by all cells in our bodies to break down large objects such as organelles and protein aggregates and to recycle their components for other processes. The overall goal of our research is to determine how the machinery involved in mediating autophagy is regulated and from the knowledge gained identify molecular strategies to increase the level of autophagy in cells. Our proposed studies focus on a protein complex called the Atg17-Atg29-Atg31 complex. The Atg17-Atg29-Atg31 complex plays a crucial role in initiating autophagy and in regulating the level of activity of this pathway. Using an advanced imaging method called single-particle electron microscopy (EM), we will capture the overall shape or detailed molecular structure of this complex. This structural information, together with results from complementary biochemical experiments, will enable us to determine how the different modules of the Atg17-Atg29-Atg31 complex are organized and how this complex performs its biological function. Upon completion, these studies will advance our molecular understanding of the Atg17-Atg29-Atg31 complex and will provide mechanistic insights into its role in autophagy regulation. In the long term, knowledge gained from our research will pave the way for the development of autophagy-targeted therapeutics for treating neurodegenerative diseases, and improve the quality of life of the large number of Canadians suffering from these disorders.