Bidirectional actin transport is influenced by microtubule and actin stability

Chetta, Joshua; Love, James M.; Bober, Brian G.; Shah, Sameer B.

doi:10.1007/s00018-015-1933-z

Cited by 9 publications

(5 citation statements)

References 76 publications

(101 reference statements)

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“…Actin patches consist of localized highly dynamic domains of actin filaments with general organization similar to lamellipodial structures (Spillane et al, 2011). Live imaging of chicken sensory neurons transfected with eYFP-actin, revealed that actin patches form spontaneously and are transient (Loudon et al, 2006; Ketschek and Gallo, 2010; Spillane et al, 2011, 2012, 2013; Sainath et al, 2016), and similar structures have been reported in other neuronal systems in vitro and in vivo (Korobova and Svitkina, 2008; Mingorance-Le Meur and O’Connor, 2009; Andersen et al, 2011; Spillane et al, 2011; Chia et al, 2014; Chetta et al, 2015; Hand et al, 2015). Actin patches serving as precursors to the formation of axonal filopodia and branches have also been imaged in vivo (Andersen et al, 2011; Spillane et al, 2011; Hand et al, 2015).…”

Section: Cytoskeletal Dynamics and Reorganization Underlying The Earlsupporting

confidence: 58%

It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches

Armijo-Weingart

Gallo

2017

Molecular and Cellular Neuroscience

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The formation of axon collateral branches from the pre-existing shafts of axons is an important aspect of neurodevelopment and the response of the nervous system to injury. This article provides an overview of the role of the cytoskeleton and signaling mechanisms in the formation of axon collateral branches. Both the actin filament and microtubule components of the cytoskeleton are required for the formation of axon branches. Recent work has begun to shed light on how these two elements of the cytoskeleton are integrated by proteins that functionally or physically link the cytoskeleton. While a number of signaling pathways have been determined as having a role in the formation of axon branches, the complexity of the downstream mechanisms and links to specific signaling pathways remain to be fully determined. The regulation of intra-axonal protein synthesis and organelle function are also emerging as components of signal-induced axon branching. Although much has been learned in the last couple of decades about the mechanistic basis of axon branching we can look forward to continue elucidating this complex biological phenomenon with the aim of understanding how multiple signaling pathways, cytoskeletal regulators and organelles are coordinated locally along the axon to give rise to a branch.

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Section: Cytoskeletal Dynamics and Reorganization Underlying The Earlsupporting

confidence: 58%

It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches

Armijo-Weingart

Gallo

2017

Molecular and Cellular Neuroscience

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“…Although the overall transport of actin in axons is well characterized, the underlying molecular mechanisms are essentially unknown. One study reported veryshortrange saltatory motion of actin densities in cultured axons 161 , but it is unclear how this bidirectional shortrange movement can lead to an overall slow, anterogradely biased transport. The actin hot spots and trails described above 148 might play a role in the axonal transport of actin; however, mecha nistic details are lacking.…”

Section: Microfluidicmentioning

confidence: 99%

The nano-architecture of the axonal cytoskeleton

2017

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The corporeal beauty of the neuronal cytoskeleton has captured the imagination of generations of scientists. One of the easiest cellular structures to visualize by light microscopy, its existence has been known for well over 100 years, yet we have only recently begun to fully appreciate its intricacy and diversity. Recent studies combining new probes with super-resolution microscopy and live imaging have revealed surprising details about the axonal cytoskeleton and, in particular, have discovered previously unknown actin-based structures. Along with traditional electron microscopy, these newer techniques offer a nanoscale view of the axonal cytoskeleton, which is important for our understanding of neuronal form and function, and lay the foundation for future studies. In this Review, we summarize existing concepts in the field and highlight contemporary discoveries that have fundamentally altered our perception of the axonal cytoskeleton.

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“…Actin dynamics is connected to many other cellular process, and of relevance to ALS/FTD, this includes axonal transport, [64][65][66] protein quality control, [67][68][69] integrated stress responses, 70 maintenance of cellular redox conditions, 31 nucleocytoplasmic shuttling, 39 and DNA damage. 35,71 Furthermore, the actin cytoskeleton supports a vast number of fundamental processes in neurons, in regulating morphogenesis and structural plasticity, axonal/dendritic initiation, axonal growth, guidance, and branching, and dendritic spine formation and stability.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated actin dynamics and cofilin correlate with TDP-43 pathology in sporadic amyotrophic lateral sclerosis

Jagaraj,

Mehta,

Parakh

et al. 2023

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disorder affecting motor neurons, that overlaps significantly with frontotemporal dementia (FTD). Most cases are sporadic (90%) with undefined aetiology, but pathological forms of TAR-binding protein 43 (TDP-43), involving its misfolding, aggregation and mislocalisation from the nucleus to the cytoplasm, are present in motor neurons in almost all cases (97%) and ∼45% FTD cases. Actin is the most abundant protein in eukaryotic cells, with structural roles in the cytoskeleton and diverse signalling functions. This includes neuronal-specific roles in dendritic spines, synapses, axonal growth cones, and plasticity. Actin is in constant dynamic equilibrium between two forms: free monomeric, globular actin (G-actin) and polymeric, filamentous actin (F-actin). Actin dynamics is regulated by several key actin-binding proteins, including tropomyosin 4.2 (Tpm4.2) and cofilin, which depolymerises actin filaments. Cofilin is activated by phosphorylation at Ser3 via LIM domain kinase1/2 (LIMK1/2), which is also regulated by phosphorylation via Rac1/cdc42. Here we demonstrate that actin dynamics is closely associated with pathological TDP-43 in ALS. More F-actin relative to G-actin was detected in lumbar spinal cords from both sporadic ALS patients and a mouse model displaying TDP-43 pathology (rNLS), and in neuronal cells expressing cytoplasmic TDP-43. Hence actin dynamics is dysregulated in sporadic ALS, resulting in more actin polymerization. We also detected increased levels of Tpm 4.2, Rac1/cdc42, and increased phosphorylation of both LIMK1/2 and cofilin, in sporadic ALS patients. TDP-43 also physically interacted with actinin vitroand in cell lysates, providing additional insights into actin dysregulation in ALS. rNLS mice display motor neuron loss and key ALS/MND behavioural phenotypes, and increased cofilin phosphorylation was also detected in these animals at symptom onset, implying that actin dynamics actively contributes to neurodegeneration. Moreover, pharmacological induction of actin polymerization produced features typical of pathological TDP-43 (cytoplasmic mis-localisation and formation of inclusions and stress granules) implying that actin dysregulation contributes to TDP-43 pathology in ALS. Importantly, we also detected more cofilin phosphorylation in spinal motor neurons from sporadic patients compared to healthy controls, revealing that our observations are clinically relevant and present in the relevant cell type. This study therefore identifies dysregulated actin dynamics as a novel disease mechanism associated with TDP-43 pathology and hence most ALS cases. It also implies that regulating cofilin or LIMK1/2 phosphorylation may be a novel therapeutic strategy in ALS, FTD and other diseases involving TDP-43 pathology.

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Bidirectional actin transport is influenced by microtubule and actin stability

Cited by 9 publications

References 76 publications

It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches

It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches

The nano-architecture of the axonal cytoskeleton

Dysregulated actin dynamics and cofilin correlate with TDP-43 pathology in sporadic amyotrophic lateral sclerosis

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