Winckler

Many diseases of the nervous system (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, Alzheimer’s disease, Huntington’s 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 aims to unravel the fundamental cellular and molecular mechanisms of how the extremely large and extraordinarily long-lived neurons overcome the challenge of regulating protein homeostasis and signaling in time and space. We are making extensive use of live imaging to understand the function and regulation of neuronal endosomes. Secondly, we are studying the cellular and 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.