The PI3,5P2 signaling pathway and neurodegeneration
Little is known about the underlying causes of neurodegeneration and other neurological diseases. Our lab recently made the unexpected discovery that altering the PI3,5P2 lipid signaling pathway to half its normal levels causes profound neurodegeneration and lethality in mice. Based on these observations we are focused on the following questions:
- How is the PI3,5P2 lipid signaling pathway regulated?
- What are the downstream effectors that are regulated by this lipid?
- Are defects in this pathway a common cause of human disease?
- Does upregulation of this pathway show therapeutic value? (If we find that it does, then we will pursue a screen that we developed for drugs that can modulate this pathway.)
The above studies are being pursued in yeast, cultured mammalian cells and mice.
How do organelles move to the correct place at the proper time?
Directed organelle movement is critical during cell division and differentiation. During cell division, a new cell-center is chosen, organelle volume doubles, and each type of organelle is accurately distributed to their proper location in the new daughter cells. Likewise during cellular differentiation, organelles move to new intracellular locations. This movement is essential for cells to acquire new functions. Defects in organelle movement have wide-ranging effects. For example defects in myosin Va based motility cause neurological diseases and defects in pigmentation, whereas defects in myosin Vb are linked to an inherited form of infant mortality.
Our lab studies yeast Myo2, a direct homologue of myosin Va and Vb. Major discoveries include our discovery of one of the first organelle-specific receptors. Analysis of the receptor showed that it is a direct target of a major cyclin-dpendent kinase, Cdk1. This is a key part of the mechanism that coordinates organelle inheritance with other cell-cycle processes, such as DNA replication. In addition we found that the spatially regulated destruction of the organelle-specific complex, is required to retain the organelle at its correct destination. Moreover, we have found a well-conserved Rab GTPase binding site on the myosin V cargo-binding domain.
We are focused on the following questions:
- What is the mechanism that underlies the spatially regulated degradation of organelle-specific complexes?
- How do Rab GTPases regulate cargo attachment to myosin V?
- Does cargo attachment require regulatory conformational changes in the cargo-binding domain of myosin V?
These questions are being pursued in yeast, yet our overall goal is to determine the mechanisms of cargo attachment to myosin V in higher eukaryotes.