The objective of this application is to determine the molecular processes by which spartin depletion leads to the accumulation of lipid droplets in neuronal cells. Our central hypotheses are that (1) spartin is involved in selective degradation of lipid droplets by autophagy, and (2) deficiency of spartin protein leads to the accumulation of lipid droplets in neurons, resulting in the pathology of Troyer syndrome. These hypotheses are based on new data from my laboratory showing that spartin recruits to the lipid droplets critical components that are important in membrane trafficking events along the autophagy pathway (namely p62 and a specific endosomal sorting complex required for transport-III protein [ESCRT-III]). We discovered that the interactions of spartin with p62 and spartin with an ESCRT-III protein are critical, because the depletion of either of these proteins results in the accumulation of lipid droplets. We also found that spartin knock-out mice show accumulation of lipid droplets in the cortex compared to wild-type animals. Once we uncover the molecular functions of spartin in lipid droplet turnover, that information will provide the foundation for developing innovative therapeutic interventions for Troyer syndrome and other neurological disorders in which the homeostasis of lipid droplets is disrupted and for prolonging normal function of axons in aging when expression level of spartin in the brain decreases.
The proposed work is important for public health because currently Troyer syndrome is incurable and causes devastating disability in affected people. This application will uncover new roles for the protein responsible for Troyer syndrome and will provide knowledge important for the development of treatments for this and other neurological disorders that have similar molecular dysfunctions. In addition, we will also learn about the processes by which cells maintain their health via turnover of specific intracellular organelles.
|Truong, Timothy; Karlinski, Zachary A; O'Hara, Christopher et al. (2015) Oxidative Stress in Caenorhabditis elegans: Protective Effects of Spartin. PLoS One 10:e0130455|
|Karlsson, Amelia B; Washington, Jacqueline; Dimitrova, Valentina et al. (2014) The role of spartin and its novel ubiquitin binding region in DALIS occurrence. Mol Biol Cell 25:1355-65|
|Renvoisé, Benoît; Stadler, Julia; Singh, Rajat et al. (2012) Spg20-/- mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling. Hum Mol Genet 21:3604-18|