F-actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

Abstract

Organelle positioning within neurites is required for proper neuronal function. In dendrites with their complex cytoskeletal organization, transport of organelles is guided by local specializations of the microtubule and actin cytoskeleton, and by coordinated activity of different motor proteins. Here, we focus on the actin cytoskeleton in the dendritic shaft and describe dense structures consisting of longitudinal and branched actin filaments. These actin patches are devoid of microtubules and are frequently located at the base of spines, or form an actin mesh around excitatory shaft synapses. Using lysosomes as an example, we demonstrate that the presence of actin patches has a strong impact on dendritic organelle transport, as lysosomes frequently stall at these locations. We provide mechanistic insights on this pausing behavior, demonstrating that actin patches form a physical barrier for kinesin-driven cargo. In addition, we identify myosin Va as an active tether which mediates long-term stalling. This correlation between the presence of actin meshes and halting of organelles could be a generalized principle by which synapses control organelle trafficking.

Role of actin in organelle trafficking in neurons

“…Positioning of organelles at specific locations is important for cellular function (van Bergeijk et al, ). Multiple lines of evidence, both in neurons and other model systems, show that the actomyosin complex can influence the positioning of organelles through (a) tethering of cargo transported by microtubule‐dependent motors to actin filaments using myosin motors (Al‐Bassam, Xu, Wandless, & Arnold, ; Janssen et al, ; Pathak, Sepp, & Hollenbeck, ; van Bommel et al, ; Wagner et al, ) or (b) a physical roadblock created by a network of actin filaments that may halt moving cargo (Chada & Hollenbeck, ; Gutnick, Banghart, West, & Schwarz, ; Kuromi & Kidokoro, ; Sood et al, ).…”

“…The actin cytoskeleton, along with Myosin V, aids in lysosome and ER positioning at microtubule‐sparse dendritic spines (van Bommel et al, ; Wagner et al, ). Actin‐rich regions at the base of dendritic spines decrease the velocity of moving lysosomes and cause their eventual stalling (van Bommel et al, ).…”

“…The actin cytoskeleton, along with Myosin V, aids in lysosome and ER positioning at microtubule‐sparse dendritic spines (van Bommel et al, ; Wagner et al, ). Actin‐rich regions at the base of dendritic spines decrease the velocity of moving lysosomes and cause their eventual stalling (van Bommel et al, ). Myosin V is seen to contribute to this stalling process as inhibition of this myosin led to a decrease in the amount of time that lysosomes remain stationary (van Bommel et al, ).…”

“…Actin‐rich regions at the base of dendritic spines decrease the velocity of moving lysosomes and cause their eventual stalling (van Bommel et al, ). Myosin V is seen to contribute to this stalling process as inhibition of this myosin led to a decrease in the amount of time that lysosomes remain stationary (van Bommel et al, ). ER entry and retention in dendritic spines is also seen to be dependent on the presence of both actin and myosin (Wagner et al, ) (Figure a).…”

“…These actin pools are distributed along axons and dendrites. Actin‐based MPS and actin hotspots/actin‐rich regions have been observed along axon and dendritic shafts (D'Este et al, ; Ganguly et al, ; van Bommel, Konietzny, Kobler, Bar, & Mikhaylova, ; Vassilopoulos et al, ; Xu et al, ). Additionally, dendritic spines show the presence of branched and bundled actin along its base, neck and head region (Hirokawa, ; Korobova & Svitkina, ; Landis & Reese, ; Markham & Fifkova, ).…”