Playing in traffic: how endosomes and lysosomes regulate dendrite growth

On behalf of Molecular Mechanisms of Neuronal Connectivity: From Membranes to Synapses' Group, Bettina Winckler from the University of Virgina will give a talk titled "Playing in traffic: how endosomes and lysosomes regulate dendrite growth" as part of the ongoing Student/Postdoc-Run Speaker Series (SPRSS).

Abstract:

Endo-lysosomal pathways are critical for proteostasis (i.e. regulating the proteome) in all cells but play particularly critical roles in neurons. Neurons are long-lived and postmitotic and thus rely particularly heavily on efficient “trash removal”. Breakdown or slowing of endo-lysosomal trafficking is associated with multiple neurodegenerative diseases as well as aging. Directional dendritic transport of late endosomes retrogradely towards the soma is required for fusion with lysosomes and for degradation in the soma. Both dendritic motility of late endosomes and somatic degradation require RAB7A. Similarly, interference with dynein function reduces motility of late endosomes and results in degradative failure. Blocking dynein function also impairs normal dendrite growth, suggesting that motility of late endosomes and/or fusion with lysosomes might be required for dendrite growth. RAB7A and dynein are mechanistically linked via RILP which is a dynein-interacting RAB7A effector. RILP also binds the late endosome-lysosome fusion tether HOPS. In non-neuronal cells, downregulation of RILP leads to deficiencies in late endosome/lysosome transport and fusion defects with lysosomes, resulting in impaired degradation. In this work, we use a separation-of-function mutant of RAB7A (RAB7AL8A) which is incapable of RILP binding to determine if RILP is the endogenous regulator of dendritic endosome motility and somatic degradation in cultured rodent hippocampal neurons of both sexes. Our data implicate endogenous RILP as a functional RAB7Adependent dynein adaptor for late endosome motility in dendrites. Surprisingly, lysosomal fusion and somatic degradation do not require RAB7A-RILP interactions. Despite the normal degradation in RAB7A-L8A expressing neurons, dendrite arborization is impaired, demonstrating that dendrite morphology defects can be separated from degradation blockade. RILP-RAB7A thus supports dendrite arborization via promoting late endosome carrier formation and retrograde transport.