Proteostasis in dendrites: Regulating endosomal flux for lysosomal degradation

Bettina Winckler is a cell biologist with a long-standing interest in polarized membrane trafficking in neurons. She received a B.A. from Swarthmore College in 1986 and a PhD in Biology from M.I.T. in 1994. As a postdoc, first in Mu-ming Poo's lab at Columbia University and then in Ira Mellman's lab at Yale University, she discovered a diffusion barrier for membrane proteins at the axon initial segment in neurons. In her own lab, first at the Mount Sinai School of Medicine and since 2004 at the University of Virginia, she established that some axonal receptors are sorted to axons not directly, but via somatodendritic endosomes, a pathway referred to as transcytosis. This discovery motivated her interests in how endocytosed receptors are sorted and transported in somatodendritic endosomes. In her most recent work, she has turned her attention to the regulation of dendritic degradative pathways.

Neurons are highly unusual cells in two regards: they are very large and very long-lived. These two characteristics of neurons pose particularly challenges for trafficking of many kinds of vesicles in axons and dendrites. Our work has focused on trafficking of endosomes in dendrites. Given the large extent of dendritic arbors, and the dispersed and highly compartmentalized organization of synapses in dendrites, one open question is where membrane receptors entering dendrites distally via endocytosis are degraded. Our results show that there is a striking spatial gradient of different endolysosomal compartments along dendrites and that distal dendrites have very limited capacity to degrade endocytosed cargos. Instead, the bulk of endocytosed cargos is transported in late endosomes to the soma where degradative lysosomes reside. We have identified Rab7 as a critical regulator of the maturation and transport of endosomes and are now investigating the roles of different Rab7 effectors downstream of Rab7 in the regulation of dendritic degradative pathways. Since many diseases of the nervous system manifest with problems in degradation and accumulate toxic aggregates, understanding the organization and regulation of dendritic degradation is of high importance.

The Endolysosomal System and Proteostasis: From Development to Degeneration.
Winckler B, Faundez V, Maday S, Cai Q, Guimas Almeida C, Zhang H.
J Neurosci. 2018 Oct 31;38(44):9364-9374.

Degradation of dendritic cargos requires Rab7-dependent transport to somatic lysosomes.
Yap CC, Digilio L, McMahon LP, Garcia ADR, Winckler B.
J Cell Biol. 2018 Sep 3;217(9):3141-3159. 

Neuronal endosomes to lysosomes: A journey to the soma.
Kulkarni VV, Maday S.
J Cell Biol. 2018 Sep 3;217(9):2977-2979.

This seminar will be livestreamed and recorded on the Fralin YouTube channel.