There are literally hundreds of cargos (including the early endosome depicted in the figure) that move long distances around the cell on microtubules. An important goal in our lab is to understand the specific mechanisms that lead to the loading, movement and offloading of these cargos.

There are two major modes of microtubule-based transport. The first (and most common) relies on cargo adaptor proteins. There are a handful of cargo adaptors, whose job is to associate with a subgroup of cargos and recruit molecular motors (left panel in figure). The identity of the motors and cargos each adaptor protein interacts with, as well as the specific regulatory mechanisms of these interactions, are largely unknown. The second mode of transport is known as hitchhiking: some cargos (including peroxisomes) move by attaching to motile endosomes at membrane-contact sites (right panel in figure). The molecular mechanisms governing these contact-site interactions are not clear. We are interested in a deeper understanding of both modes of microtubule-based transport.

Parkinson's disease (PD) is characterized by resting tremors, bradykinesia and postural instability. Cellular models of PD have defects in both vesicular trafficking and distribution of various cargos. Although it primarily affects dopaminergic neurons in the substantia nigra, it is well-appreciated that PD is a non-cell autonomous neurological disease with hallmarks of neuroinflammation. The primary mechanisms leading to aberrant vesicular trafficking and the cell-types that are most critical for PD pathophysiology are under intense investigation.

Leucine-rich repeat kinase-2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease. Importantly, LRRK2-linked PD has cellular and organismal features similar to idiopathic cases of PD: First, individuals with LRRK2-linked PD have symptoms indistinguishable from idiopathic cases. Second, LRRK2 is expressed in many cell types including neurons, astrocytes, microglia, and peripheral immune cells. Gene expression of LRRK2 is induced by inflammation. Third, LRRK2 is a kinase that phosphorylates a subset of Rab GTPases. Rabs are major directors of vesicular trafficking critical for the coordination of membrane fusion and the sorting of cellular components. We found that the movement of Rab-marked vesicles is altered in cells expressing pathogenic mutations in LRRK2 and we also found that LRRK2 acts as a roadblock in vitro to block the movement of microtubule-based motors (Check out our videos page to see the movement of Rab-marked vesicles!).