The Role of Rab Proteins in Neuronal Cells and in the Trafficking of Neurotrophin Receptors

Abstract

Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways.

Altered levels of plasma neuron‐derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury

“…The differences in NDE levels shown by the exosome biomarker protein CD81 were confirmed by counts that were 213 ± 15.7 × 10 9 /ml (mean ± sem ) for controls, 141 ± 12.8 × 10 9 /ml for acute mTBI subjects ( P < 0.0001 compared with controls), and 212 ± 14.2 × 10 9 / ml for chronic mTBI subjects. The ras‐related small GTPase RAB10 is required for formation, intracellular movements, and secretion of NDEs and some other extracellular vesicles (34). Thus it appears likely that diminished CD81‐normalized levels of RAB10 observed in NDEs of acute mTBI subjects relative to those in NDEs of chronic mTBI subjects and controls (Fig.…”

“…1). These proteins included RAB 10 that regulates formation and activities of synaptic and other neuronal vesicles (34), UCH‐L1 that facilitates removal of damaged cellular proteins (46), annexin VII and NKCC‐1 that constitute and control neuronal membrane ion transporters, as well as neuronal viability (47), and fragmented AII spectrin and claudin‐5 that maintain neuronal structure and tight‐junctions of the BBB (39, 48) (Fig. 1).…”

Exocytic and endocytic membrane trafficking in axon development

“…; Bucci et al . ; Cosker & Segal ). This retrograde signal transmission by endosomes is necessary for neurotrophin‐induced neurite outgrowth.…”

The neurotrophin receptor signaling endosome: Where trafficking meets signaling

“…In the case of TrkA, there have been reports that the signaling endosome is a Rab5‐positive early endosome, as well as reports that it is a Rab7‐positive late endosome (Delcroix et al, ; Zhang et al, ), and both might be the case. It is thought that activated TrkA in endosomes recruits and activates RabGAP5, a GAP that inactivates Rab5 (Liu et al, ; Bucci et al, ). The authors find that inactivation of Rab5 actually prolongs signaling in PC12 cells and neurite outgrowth arguing that signal duration is controlled by the residence time in the maturing endosome.…”