Cell and Developmental Biology, Neuroscience
Many diseases of the nervous system (both neurodevelopmental and neurodegenerative) as well as degenerative and regenerative processes after injury can be traced at the cellular level to disruptions of endolysosomal pathways, including autophagy. For example, Alzheimers disease, Huntingtons disease, and nerve injury all show profound defects in endosomal trafficking. This is not surprising given the central role of the endolysosomal system in regulating not only cellular trash removal, but also the quantity and quality of signaling cascades. The Winckler lab has unique expertise in studying endolysosomal trafficking in neurons and has shown that endosomes in neurons use different molecular machineries from non-polarized cells (Yap et al., 2008; Yap et al. 2010, Lasiecka et al. 2010; Yap et al. 2012; Lasiecka et al., 2014). We are particularly interested in the roles neuronal-specific proteins, (for example the neuronal-enriched endosomal protein NEEP21) play in neuronal endosomes. We are making extensive use of live imaging to understand the function and regulation of neuronal endosomes.
Secondly, we are studying the cellular mechanisms underlying the correct wiring of the nervous system in development, with an emphasis on critical cytoskeletal proteins, such as DCX (doublecortin) and nestin. DCX is genetically linked to a human neurodevelopmental disorder, Lissencephaly. We are using patient alleles of DCX to carry out structure-function analysis of DCX to arrive at a mechanistic understanding of the defects associated with these alleles.