Research topic 1: Activation of microtubule motors.
There are two classes of motors that move cargo along the microtubule track: the kinesin family of motors and cytoplasmic dynein. Our current research primarily focuses on understanding the mechanism by which dynein is activated for cargo transport. When dynein is not bound to cargo, it is kept in an inactive state. Thus, cargo binding, and the conformational changes that occur as a result, are essential for activating dynein.
Dynein does not directly bind to cargo. Rather, the motor is linked to cargo via proteins known as cargo adaptors. One such adaptor is the protein known as Bicaudal-D. This protein was first identified in Drosophila (fruit flies) but has also been shown to function as a dynein adaptor in mammalian cells. The mammalian protein is known as BICD2. Mutations in BICD2 are associated with a type of spinal muscular atrophy, a neurodegenerative disorder. Because BICD2 functions as a cargo adaptor for dynein, we hypothesized that disease-associated mutations in this protein might result in interactome changes. In essence, we speculated that these mutations might change the cargo that is linked to dynein by BICD2. In a recent publication (Neiswender et al., eLife, 2025), we demonstrated that this was indeed the case. However, not only did these disease-associated mutations result in interactome changes, they also resulted in dynein hyperactivation.
Our current studies are focused on identifying the neuronal cargo that is linked to dynein by BICD2. We plan to use the Drosophila model system for these studies. This model system should help us correlate disease-associated interactome changes with organismal phenotypes.
Research topic 2: Cytoskeletal organization
The cytoskeleton is the equivalent of an intracellular highway. Thus, to enable correct cargo delivery, the highway needs to be correctly organized. A disruption in cytoskeletal organization can, in severe circumstances, lead to cell death. More subtle disruptions can result in disease. Thus, another focus of our research is on understanding how cytoskeletal organization is established and maintained.
A key factor that contributes to cytoskeletal organization is the diverse set of proteins collectively known as cytoskeleton-associated proteins. These proteins bind to microtubules, actin, or sometimes to both cytoskeletal networks. Functions of these proteins are quite diverse; they can promote network dynamics or stability, bundle filaments together, attach filaments to the plasma membrane or organelles, and in some circumstances result in filament breakage or depolymerization.
