Mutations in LRRK2 (leucine-rich repeat kinase 2) (also known as PARK8 or dardarin) are responsible for the autosomal-dominant form of PD (Parkinson's disease). LRRK2 mutations were found in approximately 3-5% of familial and 1-3% of sporadic PD cases with the highest prevalence (up to 40%) in North Africans and Ashkenazi Jews. To date, mutations in LRRK2 are a major genetic risk factor for fam...

Vesicle trafficking is crucial for delivery of membrane compartments as well as signaling molecules to specific sites on the plasma membrane for regulation of diverse processes such as cell division, migration, polarity establishment and secretion. Rho GTPases are well-studied signaling molecules that regulate actin cytoskeleton in response to variety of extracellular stimuli. Increasing amount...

At the heart of synaptic transmission resides the synaptic vesicle cycle – a membrane trafficking pathway in which small membrane-bound vesicles mediate the release of neurotransmitter from presynaptic terminals. The cycle resembles general membrane trafficking and has three phases: vesicle filling, release and recycling. During filling, neurotransmitter is loaded into vesicles via vesicular ne...

Presynaptic nerve terminals are exquisite vesicle trafficking machines. Neurotransmission is sustained by constant recycling of a handful of vesicles. Therefore, the rate and the pathway of vesicle trafficking can critically determine synaptic efficacy during activity. However, it is yet unclear whether synaptic vesicle recycling becomes rate limiting on a rapid time scale during physiologicall...

With the 2013 Nobel Prize awarded to scientists who uncovered mechanisms of vesicular trafficking, the next big question in the field is how this process is regulated. Talks in the Minisymposium on “Regulation of Vesicle Trafficking” highlighted ways in which GTPases from the highly conserved Ypt/Rab and Arf families regulate and coordinate vesicle trafficking steps. The roles of luminal phosph...

Microtubule-based vesicle transport driven by kinesin and cytoplasmic dynein motor proteins facilitates several membrane-trafficking steps including elements of endocytosis and exocytosis in many different cell types. Most early studies on the role of microtubule-dependent vesicle transport in membrane trafficking focused either on neurons or on simple cell lines. More recently, other work has ...

Exchange of proteins at sorting endosomes is not only critical to numerous signaling pathways but also to receptor-mediated signaling and to pathogen entry into cells; however, how this process is regulated in synaptic vesicle cycling remains unexplored. In this work, we present evidence that loss of function of a single neuronally expressed GTPase activating protein (GAP), Skywalker (Sky) faci...

The exocyst (Sec6/8) complex is necessary for secretion in yeast and has been postulated to establish polarity by directing vesicle fusion to specific sites along the plasma membrane. The complex may also function in the nervous system, but its precise role is unknown. We have investigated exocyst function in Drosophila with mutations in one member of the complex, sec5. Null alleles die as grow...

Cell migration is a fundamental cellular process required for embryonic development to wound healing and also plays a key role in tumor metastasis and atherosclerosis. Migration is regulated at multiple strata, from cytoskeletal reorganization to vesicle trafficking. In migrating cells, signaling pathways are integrated with vesicle trafficking machineries in a highly coordinated fashion to acc...