Mechanisms of Polarized Organelle Distribution in Neurons

Britt, Dylan; Farı́as, Ginny G.; Guardia, Carlos M.; Bonifacino, Juan S.

doi:10.3389/fncel.2016.00088

Cited by 43 publications

(39 citation statements)

References 70 publications

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“…; dendrites and axons), together comprise the overwhelming bulk of the total cell volume, yet the cellular machinery needed for the synthesis and packaging of proteins and lipids is mainly restricted to the somatodendritic compartment (Morfini et al, 2012; Morfini et al, 2001; Pigino et al, 2012). In addition, the remarkable biochemical and functional heterogeneity observed in specific neuritic subcompartments (i.e, pre- and post-synapses, nodes of ranvier, axon hillock, etc) makes the trafficking of molecular components within neuritic processes a major requirement for neuronal function and survival (Britt et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

“…The term “ axonal transport ” (AT) refers to a wide variety of intracellular trafficking events, all required for appropriate maintenance of synaptic function and neuritic connectivity [reviewed in (Black, 2016; Britt et al, 2016; Maeder et al, 2014; Morfini et al, 2012)]. Such events include the regulated delivery of membrane- bounded organelles (MBOs) synthesized and packaged in the neuronal soma to pre- and post-synaptic compartments, as well as the removal and degradation of old materials.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

Brady

Morfini

2017

Neurobiology of Disease

118

123

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Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a “dying back” pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

Brady

Morfini

2017

Neurobiology of Disease

118

123

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“…Unlike nonpolarized cells, neurons have a soma, dendrites, and axon with different organelle compositions. Whereas some organelles are distributed throughout the neuron (e.g., mitochondria), others are largely segregated to the somatodendritic domain (e.g., the Golgi complex) or the axonal domain (e.g., synaptic vesicles) (16). Specific patterns of organelle distribution in neurons are partly the result of the organelles' ability to move along different microtubule tracks through coupling to different microtubule motors (17,18).…”

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confidence: 99%

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Farı́as

Guardia

Pace

et al. 2017

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

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The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show that an ensemble of BORC, Arl8, SKIP, and kinesin-1, previously shown to mediate centrifugal transport of lysosomes in nonneuronal cells, specifically drives lysosome transport into the axon, and not the dendrites, in cultured rat hippocampal neurons. This transport is essential for maintenance of axonal growth-cone dynamics and autophagosome turnover. Our findings illustrate how a general mechanism for lysosome dispersal in nonneuronal cells is adapted to drive polarized transport in neurons, and emphasize the importance of this mechanism for critical axonal processes.

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“…One of the best-documented examples is the sorting of various transmembrane proteins to the somatodendritic domain, which depends on interaction of tyrosine-based, dileucine-based, or noncanonical signals in the cytosolic domains of the proteins with the clathrin-associated adaptor protein 1 (AP-1) complex (6,13,(18)(19)(20) or the non-clathrin-associated AP-4 complex (21, 22). After the proteins are packaged into distinct transport carriers, the carriers themselves must be delivered to their corresponding neuronal domains, a process that is driven largely by interaction with specific microtubule motors (23,24). Axonal microtubules have a uniform orientation with their plus ends pointing toward the distal axon (25).…”

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confidence: 99%

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

Guo

Farı́as

Mattera

et al. 2016

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

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105

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An open question in cell biology is how the general intracellular transport machinery is adapted to perform specialized functions in polarized cells such as neurons. Here we illustrate this adaptation by elucidating a role for the ubiquitous small GTPase Ras-related protein in brain 5 (Rab5) in neuronal polarity. We show that inactivation or depletion of Rab5 in rat hippocampal neurons abrogates the somatodendritic polarity of the transferrin receptor and several glutamate receptor types, resulting in their appearance in the axon. This loss of polarity is not caused primarily by increased transport from the soma to the axon but rather by decreased retrieval from the axon to the soma. Retrieval is also dependent on the Rab5 effector Fused Toes (FTS)-Hook-FTS and Hook-interacting protein (FHIP) (FHF) complex, which interacts with the minus-enddirected microtubule motor dynein and its activator dynactin to drive a population of axonal retrograde carriers containing somatodendritic proteins toward the soma. These findings emphasize the importance of both biosynthetic sorting and axonal retrieval for the polarized distribution of somatodendritic receptors at steady state.Rab5 | FHF complex | dynein | neuronal polarity | retrograde transport N eurons are highly polarized cells with distinct somatodendritic and axonal domains. Synaptic inputs are received through the somatodendritic domain, integrated at the axon initial segment (AIS), and propagated along the axon for transmission to downstream cells. To accomplish these specialized functions, each neuronal domain is endowed with a distinct set of proteins. A fundamental but still largely unanswered question is how neurons establish and maintain this polarized distribution of proteins throughout their lifetimes. The available evidence indicates that the mechanisms of polarized sorting in neurons are quite complex (1-3). Newly synthesized transmembrane proteins travel together from their site of synthesis in the rough endoplasmic reticulum (ER) to the Golgi complex. Once they reach the trans-Golgi network (TGN), the proteins are sorted into different membraneenclosed transport carriers destined for the somatodendritic or axonal domains (4-8). However, the efficiency of this biosynthetic sorting varies for different proteins and is often incomplete. Other processes, such as compartment-specific retention, retrieval, or transcytosis, additionally contribute to establishing the overall distribution of proteins between the somatodendritic and axonal domains and to their localization to specialized subdomains (5, 9-17).The selective incorporation of transmembrane proteins into specialized transport carriers is a key event in the mechanisms of polarized sorting. In some cases this process is mediated by recognition of sorting signals in the cytosolic tails of the proteins by components of protein coats associated with the cytosolic face of the donor compartment. One of the best-documented examples is the sorting of various transmembrane proteins to the somatodendritic domain...

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Mechanisms of Polarized Organelle Distribution in Neurons

Cited by 43 publications

References 70 publications

Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon

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