Architecture and Dynamics of the Neuronal Secretory Network.

Regulated synthesis and movement of proteins between cellular organelles are central to diverse forms of biological adaptation and plasticity. In neurons, the repertoire of channel, receptor, and adhesion proteins displayed on the cell surface directly impacts cellular development, morphology, excitability, and synapse function. The immensity of the neuronal surface membrane and its division into distinct functional domains present a challenging landscape over which proteins must navigate to reach their appropriate functional domains. This problem becomes more complex considering that neuronal protein synthesis is continuously refined in space and time by neural activity. Here we review our current understanding of how integral membrane and secreted proteins important for neuronal function travel from their sites of synthesis to their functional destinations. We discuss how unique adaptations to the function and distribution of neuronal secretory organelles may facilitate local protein trafficking at remote sites in neuronal dendrites to support diverse forms of synaptic plasticity.

GTP-stimulated membrane fission by the N-BAR protein AMPH-1.

Membrane-enclosed transport carriers sort biological molecules between stations in the cell in a dynamic process that is fundamental to the physiology of eukaryotic organisms. While much is known about the formation and release of carriers from specific intracellular membranes, the mechanism of carrier formation from the recycling endosome, a compartment central to cellular signaling, remains to be resolved. In Caenorhabditis elegans, formation of transport carriers from the recycling endosome requires the dynamin-like, Eps15-homology domain (EHD) protein, RME-1, functioning with the Bin/Amphiphysin/Rvs (N-BAR) domain protein, AMPH-1. Here we show, using a free-solution single-particle technique known as burst analysis spectroscopy (BAS), that AMPH-1 alone creates small, tubular-vesicular products from large, unilamellar vesicles by membrane fission. Membrane fission requires the amphipathic H0 helix of AMPH-1 and is slowed in the presence of RME-1. Unexpectedly, AMPH-1-induced membrane fission is stimulated in the presence of GTP. Furthermore, the GTP-stimulated membrane fission activity seen for AMPH-1 is recapitulated by the heterodimeric N-BAR amphiphysin protein from yeast, Rvs161/167p, strongly suggesting that GTP-stimulated membrane fission is a general property of this important class of N-BAR proteins.

The cell cycle protein MAD2 facilitates endocytosis of the serotonin transporter in the neuronal soma.

Monoamine transporters retrieve serotonin (SERT), dopamine (DAT), and norepinephrine (NET) from the synaptic cleft. Transporter internalization contributes to the regulation of their surface expression. Clathrin-mediated endocytosis of plasma membrane proteins requires adaptor protein-2 (AP2), which recruits cargo to the nascent clathrin cage. However, the intracellular portions of monoamine transporters are devoid of a conventional AP2-binding site. Here, we identify a MAD2 (mitotic arrest deficient-2) interaction motif in the C-terminus of SERT, which binds the closed conformation of MAD2 and allows for the recruitment of two additional mitotic spindle assembly checkpoint (SAC) proteins, BubR1 and p31comet , and of AP2. We visualize MAD2, BubR1, and p31comet in dorsal raphe neurons, and depletion of MAD2 in primary serotonergic rat neurons decreases SERT endocytosis in the soma. Our findings do not only provide mechanistic insights into transporter internalization but also allow for rationalizing why SAC proteins are present in post-mitotic neurons.

The exocyst subunit Sec15 is critical for proper synaptic development and function at the Drosophila NMJ.

The exocyst protein complex is important for targeted vesicle fusion in a variety of cell types, however, its function in neurons is still not entirely known. We found that presynaptic knockdown (KD) of the exocyst component sec15 by transgenic RNAi expression caused a number of unexpected morphological and physiological defects in the synapse. These include the development of active zones (AZ) devoid of essential presynaptic proteins, an increase in the branching of the presynaptic arbor, the appearance of satellite boutons, and a decrease in the amplitude of stimulated postsynaptic currents as well as a decrease in the frequency of spontaneous synaptic vesicle release. We also found the release of extracellular vesicles from the presynaptic neuron was greatly diminished in the Sec15 KDs. These effects were mimicked by presynaptic knockdown of Rab11, a protein known to interact with the exocyst. sec15 RNAi expression caused an increase in phosphorylated Mothers against decapentaplegic (pMad) in the presynaptic terminal, an indication of enhanced bone morphogenic protein (BMP) signaling. Some morphological phenotypes caused by Sec15 knockdown were reduced by attenuation of BMP signaling through knockdown of wishful thinking (Wit), while other phenotypes were unaffected. Individual knockdown of multiple proteins of the exocyst complex also displayed a morphological phenotype similar to Sec15 KD. We conclude that Sec15, functioning as part of the exocyst complex, is critically important for proper formation and function of neuronal synapses. We propose a model in which Sec15 is involved in the trafficking of vesicles from the recycling endosome to the cell membrane as well as possibly trafficking extracellular vesicles for presynaptic release and these processes are necessary for the correct structure and function of the synapse.

Regulation of Hook1-mediated endosomal sorting of clathrin-independent cargo by γ-taxilin.

In clathrin-independent endocytosis, Hook1, a microtubule- and cargo-tethering protein, participates in sorting of cargo proteins such as CD98 (encoded by SLC3A2) and CD147 (encoded by BSG) into recycling endosomes. However, the molecular mechanism that regulates Hook1-mediated endosomal sorting is not fully understood. In the present study, we found that γ-taxilin is a novel regulator of Hook1-mediated endosomal sorting. γ-Taxilin depletion promoted both CD98-positive tubular formation and CD98 recycling. Conversely, overexpression of γ-taxilin inhibited the CD98-positive tubular formation. Depletion of Hook1, or Rab10 or Rab22a (which are both involved in Hook1-mediated endosomal sorting), attenuated the effect of γ-taxilin depletion on the CD98-positive tubular formation. γ-Taxilin depletion promoted CD147-mediated spreading of HeLa cells, suggesting that γ-taxilin might be a pivotal player in various cellular functions in which Hook1-mediated cargo proteins are involved. γ-Taxilin bound to the C-terminal region of Hook1 and inhibited its interaction with CD98; the latter interaction is necessary for sorting CD98. We suggest that γ-taxilin negatively regulates the sorting of Hook1-mediated cargo proteins into recycling endosomes by interfering with the interactions between Hook1 and the cargo proteins.

Tailored multivalent peptide targeting the B-subunit pentamer of cholera toxin inhibits its intestinal toxicity by inducing aberrant transport of the toxin in cells.

Cholera toxin (Ctx) is a major virulence factor produced by Vibrio cholerae that can cause gastrointestinal diseases, including severe watery diarrhea and dehydration, in humans. Ctx binds to target cells through multivalent interactions between its B-subunit pentamer and the receptor ganglioside GM1 present on the cell surface. Here, we identified a series of tetravalent peptides that specifically bind to the receptor-binding region of the B-subunit pentamer using affinity-based screening of multivalent random-peptide libraries. These tetravalent peptides efficiently inhibited not only the cell-elongation phenotype but also the elevated cAMP levels, both of which are induced by Ctx treatment in CHO cells or a human colon carcinoma cell line (Caco-2 cells), respectively. Importantly, one of these peptides, NRR-tet, which was highly efficient in these two activities, markedly inhibited fluid accumulation in the mouse ileum caused by the direct injection of Ctx. In consistent, NRR-tet reduced the extensive Ctx-induced damage of the intestinal villi. After NRR-tet bound to Ctx, the complex was incorporated into the cultured epithelial cells and accumulated in the recycling endosome, affecting the retrograde transport of Ctx from the endosome to the Golgi, which is an essential process for Ctx to exert its toxicity in cells. Thus, NRR-tet may be a novel type of therapeutic agent against cholera, which induces the aberrant transport of Ctx in the intestinal epithelial cells, detoxifying the toxin.

Endocytic recycling in plants: pathways and regulation.

Endocytic recycling is an intracellular trafficking pathway that returns endocytosed molecules to the plasma membrane via the recycling endosome. This pathway plays a crucial role in remodelling plasma membrane composition and is thus essential for cellular homeostasis. In plants, endocytic recycling regulates the localization and abundance of receptors, transporters, and channels at the plasma membrane that are involved in many aspects of plant growth and development. Despite its importance, the recycling endosome and the underlying sorting mechanisms for cargo recycling in plants remain understudied in comparison to the endocytic recycling pathways in animals. In this review, we focus on the cumulative evidence suggesting the existence of endosomes decorated by regulators that contribute to recycling in plant cells. We summarize the chemical inhibitors used for analysing cargo recycling and discuss recent advances in our understanding of how endocytic recycling participates in various plant cellular and physiological events.

Creation of Knock-In Alleles of Insulin Receptor Tagged by Fluorescent Proteins mCherry or EYFP in Fruit Fly Drosophila melanogaster.

The insulin/insulin-like growth factor-like signaling (IIS) pathway is highly conserved across metazoans and regulates numerous physiological functions, including development, metabolism, fecundity, and lifespan. The insulin receptor (InR), a crucial membrane receptor in the IIS pathway, is known to be ubiquitously expressed in various tissues, albeit at generally low levels, and its subcellular localization remains incompletely characterized. In this study, we employed CRISPR-mediated mutagenesis in the fruit fly Drosophila to create knock-in alleles of InR tagged with fluorescent proteins (InR::mCherry or InR::EYFP). By inserting the coding sequence of the fluorescent proteins mCherry or EYFP near the end of the coding sequence of the endogenous InR gene, we could trace the natural InR protein through their fluorescence. As an example, we investigated epithelial cells of the male accessory gland (AG), an internal reproductive organ, and identified two distinct patterns of InR::mCherry localization. In young AG, InR::mCherry accumulated on the basal plasma membrane between cells, whereas in mature AG, it exhibited intracellular localization as multiple puncta, indicating endocytic recycling of InR during cell growth. In the AG senescence accelerated by the mutation of Diuretic hormone 31 (Dh31), the presence of InR::mCherry puncta was more pronounced compared to the wild type. These findings raise expectations for the utility of the newly created InR::mCherry/EYFP alleles for studying the precise expression levels and subcellular localization of InR. Furthermore, this fluorescently tagged allele approach can be extended to investigate other membrane receptors with low abundance, facilitating the direct examination of their true expression and localization.

The life cycle and enigmatic egress of coronaviruses.

There has been considerable recent interest in the life cycle of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of the Covid-19 pandemic. Practically every step in CoV replication-from cell attachment and uptake via genome replication and expression to virion assembly has been considered as a specific event that potentially could be targeted by existing or novel drugs. Interference with cellular egress of progeny viruses could also be adopted as a possible therapeutic strategy; however, the situation is complicated by the fact that there is no broad consensus on how CoVs find their way out of their host cells. The viral nucleocapsid, consisting of the genomic RNA complexed with nucleocapsid proteins obtains a membrane envelope during virus budding into the lumen of the intermediate compartment (IC) at the endoplasmic reticulum (ER)-Golgi interface. From here, several alternative routes for CoV extracellular release have been proposed. Strikingly, recent studies have shown that CoV infection leads to the disassembly of the Golgi ribbon and the mobilization of host cell compartments and protein machineries that are known to promote Golgi-independent trafficking to the cell surface. Here, we discuss the life cycle of CoVs with a special focus on different possible pathways for virus egress.

Endosomal recycling tubule scission and integrin recycling involve the membrane curvature-supporting protein LITAF.

Recycling to the cell surface requires the scission of tubular membrane intermediates emanating from endosomes. Here, we identify the monotopic membrane protein LPS-induced TNF-activating factor (LITAF) and the related protein cell death involved p53 target 1 (CDIP1) as novel membrane curvature proteins that contribute to recycling tubule scission. Recombinant LITAF supports high membrane curvature, shown by its ability to reduce proteoliposome size. The membrane domains of LITAF and CDIP1 partition strongly into ∼50 nm diameter tubules labelled with the recycling markers Pacsin2, ARF6 and SNX1, and the recycling cargoes MHC class I and CD59. Partitioning of LITAF into tubules is impaired by mutations linked to Charcot Marie Tooth disease type 1C. Meanwhile, co-depletion of LITAF and CDIP1 results in the expansion of tubular recycling compartments and stabilised Rab11 tubules, pointing to a function for LITAF and CDIP1 in membrane scission. Consistent with this, co-depletion of LITAF and CDIP1 impairs integrin recycling and cell migration.

Endosomal recycling protein Rab11 in Parkin and Pink1 signaling in Drosophila model of Parkinson's disease.

Neurodegenerative diseases are progressive disorders of the nervous system primarily affecting the loss of neuronal cells present in the brain. Although most neurodegenerative cases are sporadic, some familial genes are found to be involved in the neurodegenerative diseases. The extensively studied parkin and pink1 gene products are known to be involved in the removal of damaged mitochondria via autophagy (mitophagy), a quality control process. If the function of any of these genes is somehow disrupted, accumulation of damaged mitochondria occurs in the forms of protein aggregates in the cytoplasm, leading to formation of the Lewy-bodies. Autophagy is an important catabolic process where the endosomal Rab proteins are seen to be involved. Rab11, an endosomal recycling protein, serves as an ATG9A carrier that helps in autophagosome formation and maturation. Earlier studies have reported that loss of Rab11 prevents the fusion of autophagosomes with the late endosomes hampering the autophagy pathway resulting in apoptosis of cells. In this study, we have emphasized on the importance and functional role of Rab11 in the molecular pathway of Parkin/Pink1 in Parkinson's disease.

Defining the protein and lipid constituents of tubular recycling endosomes.

Once internalized, receptors reach the sorting endosome and are either targeted for degradation or recycled to the plasma membrane, a process mediated at least in part by tubular recycling endosomes (TREs). TREs may be efficient for sorting owing to the ratio of large surface membrane area to luminal volume; following receptor segregation, TRE fission likely releases receptor-laden tubules and vesicles for recycling. Despite the importance of TRE networks for recycling, these unique structures remain poorly understood, and unresolved questions relate to their lipid and protein composition and biogenesis. Our previous studies have depicted the endocytic protein MICAL-L1 as an essential TRE constituent, and newer studies show a similar localization for the GTP-binding protein Rab10. We demonstrate that TREs are enriched in both phosphatidic acid (PA) and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), supporting the idea of MICAL-L1 recruitment by PA and Rab10 recruitment via PI(4,5)P2. Using siRNA knock-down, we demonstrate that Rab10-marked TREs remain prominent in cells upon MICAL-L1 or Syndapin2 depletion. However, depletion of Rab10 or its interaction partner, EHBP1, led to loss of MICAL-L1-marked TREs. We next used phospholipase D inhibitors to decrease PA synthesis, acutely disrupt TREs, and enable monitoring of TRE regeneration after inhibitor washout. Rab10 depletion prevented TRE regeneration, whereas MICAL-L1 knock-down did not. It is surprising that EHBP1 depletion did not affect TRE regeneration under these conditions. Overall, our study supports a primary role for Rab10 and the requirement for PA and PI(4,5)P2 in TRE biogenesis and regeneration, with Rab10 likely linking the sorting endosome to motor proteins and the microtubule network.

Sec71 separates Golgi stacks in Drosophila S2 cells.

Golgi stacks are the basic structural units of the Golgi. Golgi stacks are separated from each other and scattered in the cytoplasm of Drosophila cells. Here, we report that the ARF-GEF inhibitor Brefeldin A (BFA) induces the formation of BFA bodies, which are aggregates of Golgi stacks, trans-Golgi networks and recycling endosomes. Recycling endosomes are located in the centers of BFA bodies, while Golgi stacks surround them on their trans sides. Live imaging of S2 cells revealed that Golgi stacks repeatedly merged and separated on their trans sides, and BFA caused successive merger by inhibiting separation, forming BFA bodies. S2 cells carrying genome-edited BFA-resistant mutant Sec71M717L did not form BFA bodies at high concentrations of BFA; S2 cells carrying genome-edited BFA-hypersensitive mutant Sec71F713Y produced BFA bodies at low concentrations of BFA. These results indicate that Sec71 is the sole BFA target for BFA body formation and controls Golgi stack separation. Finally, we showed that impairment of Sec71 in fly photoreceptors induces BFA body formation, with accumulation of both apical and basolateral cargoes, resulting in inhibition of polarized transport.

Evidence for the role of Rab11-positive recycling endosomes as intermediates in coronavirus egress from epithelial cells.

After their assembly by budding into the lumen of the intermediate compartment (IC) at the endoplasmic reticulum (ER)-Golgi interface, coronaviruses (CoVs) are released from their host cells following a pathway that remains poorly understood. The traditional view that CoV exit occurs via the constitutive secretory route has recently been questioned by studies suggesting that this process involves unconventional secretion. Here, using the avian infectious bronchitis virus (IBV) as a well-established model virus, we have applied confocal microscopy to investigate the pathway of CoV egress from epithelial Vero cells. We report a novel effect of IBV infection on cellular endomembranes, namely, the compaction of the pericentrosomal endocytic recycling compartment (ERC) defined by the GTPase Rab11, which coincides with the previously described Golgi fragmentation, as well as virus release. Despite Golgi disassembly, the IC elements containing the major IBV membrane protein (M)-which mostly associates with newly formed virus particles-maintain their close spatial connection with the Rab11-positive endocytic recycling system. Moreover, partial colocalization of the M protein with Rab11 was observed, whereas M displayed negligible overlap with LAMP-1, indicating that IBV egress does not occur via late endosomes or lysosomes. Synchronization of virus release using temperature-shift protocols was accompanied by increased colocalization of M and Rab11 in vesicular and vacuolar structures in the pericentrosomal region and at the cell periphery, most likely representing IBV-containing transport carriers. In conclusion, these results add CoVs to the growing list of viruses exploiting the endocytic recycling apparatus defined by Rab11 for their assembly and/or release.

Endocytosis of the non-catalytic ADAM23: Recycling and long half-life properties.

A Disintegrin And Metalloprotease 23 (ADAM23) is a member of the ADAMs family of transmembrane proteins, mostly expressed in nervous system, and involved in traffic and stabilization of Kv1-potassium channels, synaptic transmission, neurite outgrowth, neuronal morphology and cell adhesion. Also, ADAM23 has been linked to human pathological conditions, such as epilepsy, cancer metastasis and cardiomyopathy. ADAM23 functionality depends on the molecule presence at the cell surface and along the secretory pathway, as expected for a cell surface receptor. Because endocytosis is an important functional regulatory mechanism of plasma membrane receptors and no information is available about the traffic or turnover of non-catalytic ADAMs, we investigated ADAM23 internalization, recycling and half-life properties. Here, we show that ADAM23 undergoes constitutive internalization from the plasma membrane, a process that depends on lipid raft integrity, and is redistributed to intracellular vesicles, especially early and recycling endosomes. Furthermore, we observed that ADAM23 is recycled from intracellular compartments back to the plasma membrane and thus has longer half-life and higher cell surface stability compared with other ADAMs. Our findings suggest that regulation of ADAM23 endocytosis/stability could be exploited therapeutically in diseases in which ADAM23 is directly involved, such as epilepsy, cancer progression and cardiac hypertrophy.

Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 is a novel positive modulator of autophagy and stabilizes cellular protein homeostasis.

The cellular protein homeostasis (proteostasis) network responds effectively to insults. In a functional screen in C. elegans, we recently identified the gene receptor-mediated endocytosis 8 (rme-8; human ortholog: DNAJC13) as a component of the proteostasis network. Accumulation of aggregation-prone proteins, such as amyloid-ß 42 (Aß), α-synuclein, or mutant Cu/Zn-superoxide dismutase (SOD1), were aggravated upon the knockdown of rme-8/DNAJC13 in C. elegans and in human cell lines, respectively. DNAJC13 is involved in endosomal protein trafficking and associated with the retromer and the WASH complex. As both complexes have been linked to autophagy, we investigated the role of DNAJC13 in this degradative pathway. In knockdown and overexpression experiments, DNAJC13 acts as a positive modulator of autophagy. In contrast, the overexpression of the Parkinson's disease-associated mutant DNAJC13(N855S) did not enhance autophagy. Reduced DNAJC13 levels affected ATG9A localization at and its transport from the recycling endosome. As a consequence, ATG9A co-localization at LC3B-positive puncta under steady-state and autophagy-induced conditions is impaired. These data demonstrate a novel function of RME-8/DNAJC13 in cellular homeostasis by modulating ATG9A trafficking and autophagy.

Acylpeptide hydrolase is a novel regulator of KRAS plasma membrane localization and function.

The primary site for KRAS signaling is the inner leaflet of the plasma membrane (PM). We previously reported that oxanthroquinone G01 (G01) inhibited KRAS PM localization and blocked KRAS signaling. In this study, we identified acylpeptide hydrolase (APEH) as a molecular target of G01. APEH formed a stable complex with biotinylated G01, and the enzymatic activity of APEH was inhibited by G01. APEH knockdown caused profound mislocalization of KRAS and reduced clustering of KRAS that remained PM localized. APEH knockdown also disrupted the PM localization of phosphatidylserine (PtdSer), a lipid critical for KRAS PM binding and clustering. The mislocalization of KRAS was fully rescued by ectopic expression of APEH in knockdown cells. APEH knockdown disrupted the endocytic recycling of epidermal growth factor receptor and transferrin receptor, suggesting that abrogation of recycling endosome function was mechanistically linked to the loss of KRAS and PtdSer from the PM. APEH knockdown abrogated RAS-RAF-MAPK signaling in cells expressing the constitutively active (oncogenic) mutant of KRAS (KRASG12V), and selectively inhibited the proliferation of KRAS-transformed pancreatic cancer cells. Taken together, these results identify APEH as a novel drug target for a potential anti-KRAS therapeutic.

The integral function of the endocytic recycling compartment is regulated by RFFL-mediated ubiquitylation of Rab11 effectors.

Endocytic trafficking is regulated by ubiquitylation (also known as ubiquitination) of cargoes and endocytic machineries. The role of ubiquitylation in lysosomal delivery has been well documented, but its role in the recycling pathway is largely unknown. Here, we report that the ubiquitin (Ub) ligase RFFL regulates ubiquitylation of endocytic recycling regulators. An RFFL dominant-negative (DN) mutant induced clustering of endocytic recycling compartments (ERCs) and delayed endocytic cargo recycling without affecting lysosomal traffic. A BioID RFFL interactome analysis revealed that RFFL interacts with the Rab11 effectors EHD1, MICALL1 and class I Rab11-FIPs. The RFFL DN mutant strongly captured these Rab11 effectors and inhibited their ubiquitylation. The prolonged interaction of RFFL with Rab11 effectors was sufficient to induce the clustered ERC phenotype and to delay cargo recycling. RFFL directly ubiquitylates these Rab11 effectors in vitro, but RFFL knockout (KO) only reduced the ubiquitylation of Rab11-FIP1. RFFL KO had a minimal effect on the ubiquitylation of EHD1, MICALL1, and Rab11-FIP2, and failed to delay transferrin recycling. These results suggest that multiple Ub ligases including RFFL regulate the ubiquitylation of Rab11 effectors, determining the integral function of the ERC.

An update on cellular and molecular determinants of Parkinson's disease with emphasis on the role of the retromer complex.

Parkinson's disease (PD) is a highly prevalent neurodegenerative condition. The disease involves the progressive degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Among late-onset, familial forms of Parkinson are cases with mutations in the PARK17 locus encoding the vacuolar protein sorting 35 (Vps35), a subunit of the retromer complex. The retromer complex is composed of a heterotrimeric protein core (Vps26-Vps35-Vps29). The best-known role of retromer is the retrieval of cargoes from endosomes to the Golgi complex or the plasma membrane. However, recent literature indicates that retromer performs roles associated with lysosomal and mitochondrial functions and degradative pathways such as autophagy. A common point mutation affecting the retromer subunit Vps35 is D620N, which has been linked to the alterations in the aforementioned cellular processes as well as with neurodegeneration. Here, we review the main aspects of the malfunction of the retromer complex and its implications for PD pathology. Besides, we highlight several controversies still awaiting clarification.

Rab11-mediated recycling endosome role in nervous system development and neurodegenerative diseases.

STUDY: Membrane trafficking process is significant for the complex and precise regulatory of the nervous system. Rab11, as a small GTPase of the Rab superfamily, controls endocytic vesicular trafficking to the cell surface after sorting in recycling endosome (RE), coordinating with its receptors to maintain neurological function. MATERIALS AND METHODS: This article reviewed the literature of Rab11 in nervous system. RESULTS: Rab11-positive vesicles targeted transport growth-related molecules, such as integrins, protrudin, tropomyosin receptor kinase (Trk) A/B receptor and AMPA receptor (AMPAR) to membrane surface to promote the regeneration capacity of axon and dendrites and maintain synaptic plasticity. In addition, many studies have shown that the expression of Rab11 is decreased in multiple neurodegenerative diseases, which is highly correlated with the process of production, transport and clearance of disease-related pathological proteins. And overexpression or increased activity of Rab11 can greatly improve the defect of membrane trafficking and slow down the disease process. CONCLUSION: With increasing research efforts on Rab11-dependent membrane trafficking mechanisms, a potential target for nerve regeneration and neurodegenerative diseases will be provided.