Neuronal protein trafficking: Emerging consequences of endoplasmic reticulum dynamics

Valenzuela, Juan Pablo; Jaureguiberry‐Bravo, Matias; Couve, Andrés

doi:10.1016/j.mcn.2011.07.001

Cited by 18 publications

(15 citation statements)

References 114 publications

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“…Axon elongation is a consequence of the interplay between force generation at the growth cone that pulls the axon forward, pushing forces due to microtubule and actin polymerization and depolymerization, the rate of protein synthesis at the cell body, and the action of cytoskeletal motors (Baas and Ahmad, 2001;Goldberg, 2003;Lamoureux et al, 1989;Mitchison and Kirschner, 1988;O'Toole et al, 2008;Suter and Miller, 2011). Several models of axonal elongation have focused on the sequence of processes based on the production of tubulin dimers at the cell body, the active transport of these proteins to the the tip of the growing axon, and microtubule extension at the growth cone (Graham et al, 2006;Kiddie et al, 2005;McLean and Graham, 2004;Miller and Samulels, 1997;van Veen and van Pelt, 1994). One motivation for identifying the polymerization of microtubules as a rate limiting step is that axonal growth occurs at a similar rate to the slow axonal transport of tubulin, namely, around 1mm per day.…”

Section: Transport and Self-organization In Cellsmentioning

confidence: 99%

“…The extensive secretory pathway of eukaryotic cells provides an alternative system for transporting newly synthesized lipids and proteins along axons and dendrites (Kennedy and Ehlers, 2006;Ramirez and Couve, 2011;Valenzuela et al, 2011). One major organelle of the secretory pathway is the endoplasmic reticulum (ER), which tends to be dispersed throughout the cytoplasm of a cell (Lippincott-Schwartz et al, 2000), see Fig.…”

Section: Transport and Self-organization In Cellsmentioning

confidence: 99%

“…The diffusivity of proteins within the tubular-like SER is 3-6 times smaller than within the cytoplasm. However, the ER is constantly being remodeld by motor-driven sliding along microtubules, for example, which could add an active component to protein transport (Ramirez and Couve, 2011;Valenzuela et al, 2011). Moreover, the thin tubular structure of the SER reduces the effective spatial dimension of diffusion, thus enhancing progression along a dendrite.…”

Section: Transport and Self-organization In Cellsmentioning

confidence: 99%

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Stochastic models of intracellular transport

2013

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The interior of a living cell is a crowded, heterogenuous, fluctuating environment. Hence, a major challenge in modeling intracellular transport is to analyze stochastic processes within complex environments. Broadly speaking, there are two basic mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an over-damped Brownian particle. On the other hand, active transport requires chemical energy, usually in the form of ATP hydrolysis, and can be direction specific, allowing biomolecules to be transported long distances; this is particularly important in neurons due to their complex geometry. In this review we present a wide range of analytical methods and models of intracellular transport. In the case of diffusive transport, we consider narrow escape problems, diffusion to a small target, confined and single-file diffusion, homogenization theory, and fractional diffusion. In the case of active transport, we consider Brownian ratchets, random walk models, exclusion processes, random intermittent search processes, quasisteady-state reduction methods, and mean field approximations. Applications include receptor trafficking, axonal transport, membrane diffusion, nuclear transport, protein-DNA interactions, virus trafficking, and the self-organization of subcellular structures.

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Section: Transport and Self-organization In Cellsmentioning

confidence: 99%

Section: Transport and Self-organization In Cellsmentioning

confidence: 99%

Section: Transport and Self-organization In Cellsmentioning

confidence: 99%

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Stochastic models of intracellular transport

2013

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“…The ER is comprised of a network of membrane tubules and sheetlike cisternae that extend throughout the cytoplasm and encase the nucleus (7)(8)(9). Several factors contribute to this architecture, including (i) membrane-bending proteins of the REEP and reticulon families; (ii) regulators of the microtubule cytoskeleton, which governs the spatial patterning of the ER network; and (iii) components of the early secretory pathway that control vesicle biogenesis and egress (10)(11)(12)(13)(14)(15)(16). Among the best-characterized HSP genes are SPAST, ATL1, and REEP1, all of which encode proteins (spastin, atlastin-1, and REEP1, respectively) that potentially regulate ER organization.…”

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confidence: 99%

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

Beetz

Johnson

Schuh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.membrane trafficking | COPII-mediated secretion | ER exit site H ereditary spastic paraplegias (HSPs) are a diverse group of disorders characterized by spastic weakness in the lower extremities, which results from degeneration of upper motoneuron axons in the corticospinal tract (1, 2). Based on the presence or absence of other neurological abnormalities, HSPs are classified as complicated or pure, respectively. In addition to lower-limb spasticity, complicated forms of HSP may be associated with ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction, and/or epilepsy. HSPs are typically progressive, but age of onset is highly variable. The heterogeneity in clinical presentation is accompanied by genetic heterogeneity. To date, more than 40 different genetic loci, which include nearly all modes of inheritance, have been linked to HSPs (1-5). However, in nearly half of these cases, the identities of the causative genes remain unknown. The identification of additional HSP genes and, more importantly, the functional characterization of their encoded products, will both contribute to our understanding of the pathomechanisms underlying HSPs and reveal the general requirements for lifelong axonal maintenance.More than half the HSP cases in North America and Northern Europe can be attributed to defects in organelle dynamics (6). In particular, mutations that impact the architecture of the endoplasmic reticulum (ER) are common in patients with HSP. The ER is comprised of a network of membrane tubules and sheetlike cisternae that extend throughout the cytoplasm and encase the nucleus (7-9). Several factors contribute to this architecture, including (i) membrane-bending proteins of the REEP and reticulon families; (ii) regulators of the microtubule cytoskeleton, which governs the spatial patterning of the ER network; and (iii) components of the ear...

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“…Whereas the ribosomes-enriched ER (rough ER) is observed in the cell soma, dendrites, and initial axon segments, the axon is filled with smooth ER (24,25). The axonal ER network is a highly dynamic structure that is constantly remodeled and extended through interaction with microtubules, kinesin-1 and dynein molecular motors (26,27).…”

Section: Figmentioning

confidence: 99%

Signaling Over Distances

Saito

Cavalli

2016

Molecular & Cellular Proteomics

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Neurons are extremely polarized cells. Axon lengths often exceed the dimension of the neuronal cell body by several orders of magnitude. These extreme axonal lengths imply that neurons have mastered efficient mechanisms for long distance signaling between soma and synaptic terminal. These elaborate mechanisms are required for neuronal development and maintenance of the nervous system. Neurons can fine-tune long distance signaling through calcium wave propagation and bidirectional transport of proteins, vesicles, and mRNAs along microtubules. The signal transmission over extreme lengths also ensures that information about axon injury is communicated to the soma and allows for repair mechanisms to be engaged. This review focuses on the different mechanisms employed by neurons to signal over long axonal distances and how signals are interpreted in the soma, with an emphasis on proteomic studies. We also discuss how proteomic approaches could help further deciphering the signaling mechanisms operating over long distance in axons. Neurons have unique and highly polarized morphologies. The axon allows intracellular communication between the cell soma and the distantly located synaptic terminal. The extreme length of axons relative to the cell soma diameter poses great challenges for neuronal development, maintenance, and repair. Anterograde and retrograde axonal transport of proteins vesicles and RNA along the microtubule tracks in the axon is crucial to sustain the required signaling events underlying development and maintenance of the nervous system. The retrograde transport system is also used following axon injury to communicate information from the site of injury back to the soma. Communication between distant axon locations and the cell soma is also ensured by a more rapid signal encoded in calcium waves. Incoming signals from distant axon locations are interpreted by the soma to regulate gene expression for survival or repair. The neuronal epigenome is also influenced by incoming signals to appropriately coordinate transcriptional responses. In this review, we discuss the state of the field regarding the different mechanisms employed by neurons to signal intracellularly over long distances in axons and how signals are interpreted in the cell soma, with an emphasis on proteomic studies. We also discuss how the use of proteomics could further help in understanding long distance signaling system in axons. The communication employed by neurons to signal along dendrites has been reviewed in detail elsewhere (1) and will not be discussed here.Calcium Influx, Back Propagation, and Long Distance Effects-Alterations in axonal calcium levels affect multiple and diverse signaling events, including local protein synthesis and degradation. These local signals can have long distance effects. Axon injury provides a powerful system to study the role of calcium in axonal signaling, because injury-induced calcium influx in the axon triggers important downstream events at the injury site and the soma (Fig.

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Neuronal protein trafficking: Emerging consequences of endoplasmic reticulum dynamics

Cited by 18 publications

References 114 publications

Stochastic models of intracellular transport

Stochastic models of intracellular transport

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure

Signaling Over Distances

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