Recent super-resolution microscopy studies have unveiled a periodic scaffold of actin rings regularly spaced by spectrins under the plasma membrane of axons. However, ultrastructural details are unknown, limiting a molecular and mechanistic understanding of these enigmatic structures. Here, we combine platinum-replica electron and optical super-resolution microscopy to investigate the cortical cytoskeleton of axons at the ultrastructural level. Immunogold labeling and correlative super-resolution/electron microscopy allow us to unambiguously resolve actin rings as braids made of two long, intertwined actin filaments connected by a dense mesh of aligned spectrins. This molecular arrangement contrasts with the currently assumed model of actin rings made of short, capped actin filaments. Along the proximal axon, we resolved the presence of phospho-myosin light chain and the scaffold connection with microtubules via ankyrin G. We propose that braided rings explain the observed stability of the actin-spectrin scaffold and ultimately participate in preserving the axon integrity. The ultrastructural details of the periodic scaffold of actin rings under the plasma membrane of axons remain unknown. Here, the authors combine platinum-replica electron and optical super-resolution microscopy and resolve actin rings as braids made of two long, intertwined actin filaments connected by a dense mesh of aligned spectrins.

/pdf/ultrastructure-of-the-axonal-periodic-scaffold-reveals-a-hheblkv0rn.pdf

Ultrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings.

The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers.

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells. Supplementary figures.

Most mammalian neurons have a narrow axon, which constrains the passage of large cargoes such as autophagosomes that can be larger than the axon diameter. Radial axonal expansion must therefore occur to ensure efficient axonal trafficking. In this study, we reveal that the speed of various large cargoes undergoing axonal transport is significantly slower than that of small ones and that the transit of diverse-sized cargoes causes an acute, albeit transient, axonal radial expansion, which is immediately restored by constitutive axonal contractility. Using live super-resolution microscopy, we demonstrate that actomyosin-II controls axonal radial contractility and local expansion, and that NM-II filaments associate with periodic F-actin rings via their head domains. Pharmacological inhibition of NM-II activity significantly increases axon diameter by detaching the NM-II from F-actin and impacts the trafficking speed, directionality, and overall efficiency of long-range retrograde trafficking. Consequently, prolonged NM-II inactivation leads to disruption of periodic actin rings and formation of focal axonal swellings, a hallmark of axonal degeneration.

Radial contractility of actomyosin rings facilitates axonal trafficking and structural stability

Cancer is a complex disease that causes abnormal genetic changes and unchecked cellular growth. It also causes a disruption in the normal regulatory processes that leads to the creation of malignant tissue. The complex interplay of genetic, environmental, and epigenetic variables influences its etiology. Long non-coding RNAs (LncRNAs) have emerged as pivotal contributors within the intricate landscape of cancer biology, orchestrating an array of multifaceted cellular processes that substantiate the processes of carcinogenesis and metastasis. Metastasis is a crucial driver of cancer mortality. Among these, MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) has drawn a lot of interest for its function in encouraging metastasis via controlling the Epithelial-Mesenchymal Transition (EMT) procedure. MALAT1 exerts a pivotal influence on the process of EMT, thereby promoting metastasis to distant organs. The mechanistic underpinning of this phenomenon involves the orchestration of an intricate regulatory network encompassing transcription factors, signalling cascades, and genes intricately associated with the EMT process by MALAT1. Its crucial function in transforming tumor cells into an aggressive phenotype is highlighted by its capacity to influence the expression of essential EMT effectors such as N-cadherin, E-cadherin, and Snail. An understanding of the MALAT1-EMT axis provides potential therapeutic approaches for cancer intervention. Targeting MALAT1 or its downstream EMT effectors may reduce the spread of metastatic disease and improve the effectiveness of already available therapies. Understanding the MALAT1-EMT axis holds significant clinical implications. Therefore, directing attention towards MALAT1 or its downstream mediators could present innovative therapeutic strategies for mitigating metastasis and improving patient prognosis. This study highlights the importance of MALAT1 in cancer biology and its potential for cutting back on metastatic disease with novel treatment strategies. 

From LncRNA to Metastasis: The MALAT1-EMT axis in cancer progression

https://research.abo.fi/ws/files/25135613/EJPB_Manuscript_FTY720%20and%20MTX%20multidrug%20for%20ARTUR.pdf

Nanoparticles carrying fingolimod and methotrexate enables targeted induction of apoptosis and immobilization of invasive thyroid cancer

Tropomyosin Tpm3.1 Is Required to Maintain the Structure and Function of the Axon Initial Segment

The axon initial segment (AIS) is the site of action potential initiation and serves as a vesicular filter and diffusion barrier that help maintain neuronal polarity. Recent studies have revealed details about a specialized structural complex in the AIS. While an intact actin cytoskeleton is required for AIS formation, pharmacological disruption of actin polymerization compromises the AIS vesicle filter but does not affect overall AIS structure. In this study, we found that the tropomyosin isoform Tpm3.1 decorates a population of relatively stable actin filaments in the AIS. Inhibiting Tpm3.1 in cultured hippocampal neurons led to the loss of AIS structure, the AIS vesicle filter, the clustering of sodium ion channels, and reduced firing frequency. We propose that Tpm3.1-decorated actin filaments form a stable actin filament network under the AIS membrane which provides a scaffold for membrane organization and AIS proteins.

https://www.biorxiv.org/content/biorxiv/early/2019/07/23/711614.1.full.pdf

Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment

The axon initial segment (AIS) comprises a sub-membranous lattice containing periodic actin rings. The overall AIS structure is insensitive to actin-disrupting drugs, but the effects of actin-disrupting drugs on actin rings lack consensus. We examined the effect of latrunculin A and B on the actin cytoskeleton of neurons in culture and actin rings in the AIS. Both latrunculin A and B markedly reduced the overall amount of F-actin in treated neurons in a dose-dependent manner, but the periodicity of actin rings remained unaffected. The insensitivity of AIS actin rings to latrunculin suggests they are relatively stable.

Sub-membranous actin rings in the axon initial segment are resistant to the action of latrunculin.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

David Micinski

Author Tools

Chat about Author

Papers

Tropomyosin Tpm3.1 Is Required to Maintain the Structure and Function of the Axon Initial Segment

Tropomyosin Tpm3.1 is required to maintain the structure and function of the axon initial segment

Sub-membranous actin rings in the axon initial segment are resistant to the action of latrunculin.