The supramolecular landscape of growing human axons

Hoffmann, Patrick C.; Giandomenico, Stefano L.; Ganeva, Iva; Wozny, Michael R.; Sutcliffe, Magdalena; Kukulski, Wanda; Lancaster, Madeline A.

doi:10.1101/2020.07.23.216622

Cited by 4 publications

(4 citation statements)

References 50 publications

(71 reference statements)

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“…The narrow tubules were present in 30 tomograms and had undulating shape, where the two lipid bilayers come in contact. This “beaded” morphology is also reported in a recent study of human axons (Hoffmann et al, 2020). In 8 tomograms we found electron dense deposits in the ER lumen (Figure S2A).…”

Section: Resultssupporting

confidence: 84%

“…While microtubules typically extended beyond the imaged volume, actin filaments were short, with an average length of 250 nm (Figure S1C). Similar to a recent cryo-ET study of human organoid axons (Hoffmann et al, 2020), the observed actin filaments ran roughly parallel to the microtubule network rather than forming rings around the axon shaft. This actin may correspond to “deep” actin which is dynamic and is transported slowly through axons (Chakrabarty et al, 2018; Ganguly et al, 2015).…”

Section: Resultssupporting

confidence: 83%

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A cryo-ET survey of intracellular compartments within mammalian axons

Foster

2021

Preprint

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The neuronal axon contains many intracellular compartments which travel between the cell body and axon tip. The nature of these cargos and the complex axonal environment through which they traverse is unclear. Here, we describe the internal components of mammalian sensory axons using cryo-electron tomography. We show that axonal endoplasmic reticulum has thin, beaded appearance and is tethered to microtubules at multiple sites. The tethers are elongated, ~7 nm long proteins which cluster in small groups. We survey the different membrane-bound cargos in axons, quantify their abundance and describe novel internal features including granules and broken membranes. We observe connecting density between membranes and microtubules which may correspond to motor proteins. In addition to membrane-bound organelles, we detect numerous proteinaceous compartments, including vaults and previously undescribed virus-like capsid particles. The abundance of these compartments suggests they undergo trafficking in axons. Our observations outline the physical characteristics of axonal cargo and provide a platform for identification of their constituents.

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Section: Resultssupporting

confidence: 84%

Section: Resultssupporting

confidence: 83%

A cryo-ET survey of intracellular compartments within mammalian axons

Foster

2021

Preprint

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“…The ultrastructural detail of EM is needed to answer such a question, but decades of EM studies could not discern the submembrane periodic scaffold [2]. It is likely that classical thin-section EM cannot easily contrast actin assemblies made of a few filaments -and more recent cryoEM approaches also failed to visualize the MPS along axons [39,40].…”

Section: Molecular Organization Of the Mpsmentioning

confidence: 99%

Putting the axonal periodic scaffold in order

Leterrier

2021

Current Opinion in Neurobiology

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Neurons rely on a unique organization of their cytoskeleton to build, maintain and transform their extraordinarily intricate shapes. After decades of research on the neuronal cytoskeleton, it is exciting that novel assemblies are still discovered thanks to progress in cellular imaging methods. Indeed, super-resolution microscopy has revealed that axons are lined with a periodic scaffold of actin rings, spaced every 190 nm by spectrins. Determining the architecture, composition, dynamics, and functions of this membraneassociated periodic scaffold is a current conceptual and technical challenge, as well as a very active area of research. This short review aims at summarizing the latest research on the axonal periodic scaffold, highlighting recent progress and open questions.

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“…Developing axons can be subdivided into axon shaft and growth cone. While the former compartment has been proposed to have predominantly a structural role and is enriched in cytoskeletal components and tubular endoplasmic reticulum [105], the latter compartment, which senses and responds to guidance cues, is characterized by a dynamic actin cytoskeleton, the presence of mRNA, polysomes, UPS components, endo-and exocytic vesicles [106,107].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Proteostatic regulation in neuronal compartments

Giandomenico

Álvarez-Castelao

Schuman

2022

Trends in Neurosciences

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Neurons continuously adapt to external cues and challenges, including stimulation, plasticity-inducing signals and aging. These adaptations are critical for neuronal physiology and extended survival. Proteostasis is the process by which cells adjust their protein content to achieve the specific protein repertoire necessary for cellular function. Due to their complex morphology and polarized nature, neurons possess unique proteostatic requirements. Proteostatic control in axons and dendrites must be implemented through regulation of protein synthesis and degradation in a decentralized fashion, but at the same time, it requires integration, at least in part, in the soma. Here, we discuss current understanding of neuronal proteostasis, as well as open questions and future directions requiring further exploration. The challenge of regulating a distant proteomeMost catalyzed chemical reactions inside cells depend on protein levels, and fine-tuning protein concentrations is key to ensure proper cellular function. Because throughout the cellular lifespan proteins accumulate damage, become dysfunctional and need to be replaced continually, protein synthesis and protein turnover are central to cellular physiology and function. The dynamic regulation of a balanced and functional proteome (i.e., proteostasis) concerns all proteins whose levels need to be adjusted in space and time in response to intracellular and extracellular cues. Thus, the specific parameters of cellular proteostasis vary across cell types and states. However, cellular proteostasis invariably relies on the precise control of protein synthesis, folding and conformational maintenance, post-translational modifications (PTMs), degradation, and secretion [1]. Precise control of these parameters is already challenging in cells that have little or no polarity, but becomes a particularly impressive feat for highly polarized cells, such as neurons.Neurons stand out from all other cell types in their unique morphology and high degree of compartmentalization; characteristics that are central to neuronal computation. Often, extrinsic signals are spatially localized so that only a confined portion of the neuron receives a certain signal, with the neuronal portion being, for instance, a cluster of dendrites (influenced by a neuromodulator), a single dendritic branch, a synaptic neighborhood, or even an individual synapse. How these local signals are transmitted to the somata remains largely unknown. Work over the last two decades has shown that neurons have the capacity to tune their proteome locally through regulation of local protein synthesis, degradation, and PTMs to regulate multiple aspects of dendritic and axonal biology [2]. Nevertheless, to date, we still lack a comprehensive understanding of how different cellular degradation pathways interact with the protein synthesis machinery to shape and maintain the local proteome.In this review, we discuss current understanding of neuronal local proteostatic regulation, and key knowledge gaps in the field. We also com...

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The supramolecular landscape of growing human axons

Cited by 4 publications

References 50 publications

A cryo-ET survey of intracellular compartments within mammalian axons

A cryo-ET survey of intracellular compartments within mammalian axons

Putting the axonal periodic scaffold in order

Proteostatic regulation in neuronal compartments

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