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Biomedicines
Special Issues
New Perspectives on Neuronal Cytoskeletal Dysregulation in Health and Disease
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New Perspectives on Neuronal Cytoskeletal Dysregulation in Health and Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 4224

Special Issue Editors

Dr. Arjun Singh

E-Mail Website
Guest Editor
Molecular Pharmacology Program, Laboratory of Signal Transduction, Mortimer B. Zuckerman Research Center, 417 East 68th Street, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Interests: molecular pharmacology; cancer pharmacology; natural products; ethnomedicine
Special Issues, Collections and Topics in MDPI journals
Dr. Rajvir Singh

E-Mail Website
Guest Editor
Molecular Pharmacology Program, Laboratory of Signal Transduction, Mortimer B. Zuckerman Research Center, 417 East 68th Street, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Interests: cell metabolism; cell biology; cardiovascular; CNS disorders; inflammation in neuronal structure

Special Issue Information

Dear Colleagues,

Neurons have distinct and specialized morphological characteristics that allow them to receive, process, and transmit information. Because axons in humans can extend up to one meter in length, the presence of both the neuronal cytoskeleton and mitochondria is required to establish and maintain the polarity and physiological properties of these enormous structures. The neuronal cytoskeleton is made up of actin filaments, intermediate filaments, and microtubules, which help to transmit electrical and chemical signals between neurons and regulate the balance between motility and stability in neuronal structures.

Articles focused on understanding the pathophysiology of the neuronal cytoskeleton and Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and many other neurodegenerative diseases and/or their synergistic effects during CNS disorders are welcome in this Special Issue.

Specific aims of this Special Issue:

To publish original research, review articles, and commentaries on the below topics:

  • Mitochondria play such an important role in adenosine triphosphate (ATP) production, metabolite synthesis, calcium homeostasis, and local protein synthesis, and proper localization of these organelles is critical for maintaining neural connections.
  • Interactions between mitochondria and cytoskeletal motor proteins are thus critical for establishing long-distance transport and positioning of mitochondria along the axon and within dendrites.
  • Changes in the levels, dynamics, and stability of cytoskeletal proteins of mutations or alterations in molecular pathways involved.
  • Axonal transport is linked to the formation of protein aggregates in central nervous system (CNS) neurons and glia.
  • Protein aggregates are a common pathological feature of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and many other neurodegenerative diseases.
  • These findings point to a pathogenic link between the early stages of neurodegenerative processes and dysregulated transport of vesicles and cargos (mRNA and growth factors).
  • Impaired mitochondrial trafficking, and neurofilament accumulation within the axon.

Clearly, it is critical to investigate new molecular pathways that underpin this relationship, which could be used as novel therapeutic targets or to provide insight into common pathways involved in the neurodegenerative process.

Dr. Arjun Singh
Dr. Rajvir Singh
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuronal cytoskeleton
  • Alzheimer's disease (AD)
  • Parkinson's disease (PD)
  • Huntington's disease (HD)
  • neurodegenerative diseases

Published Papers (2 papers)

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Research

25 pages, 4204 KiB  
Article
Chemokine Receptor Antagonists Prevent and Reverse Cofilin-Actin Rod Pathology and Protect Synapses in Cultured Rodent and Human iPSC-Derived Neurons
by Thomas B. Kuhn, Laurie S. Minamide, Lubna H. Tahtamouni, Sydney A. Alderfer, Keifer P. Walsh, Alisa E. Shaw, Omar Yanouri, Henry J. Haigler, Michael R. Ruff and James R. Bamburg
Biomedicines 2024, 12(1), 93; https://doi.org/10.3390/biomedicines12010093 - 1 Jan 2024
Cited by 1 | Viewed by 2124
Abstract
Synapse loss is the principal cause of cognitive decline in Alzheimer’s disease (AD) and related disorders (ADRD). Synapse development depends on the intricate dynamics of the neuronal cytoskeleton. Cofilin, the major protein regulating actin dynamics, can be sequestered into cofilactin rods, intra-neurite bundles [...] Read more.
Synapse loss is the principal cause of cognitive decline in Alzheimer’s disease (AD) and related disorders (ADRD). Synapse development depends on the intricate dynamics of the neuronal cytoskeleton. Cofilin, the major protein regulating actin dynamics, can be sequestered into cofilactin rods, intra-neurite bundles of cofilin-saturated actin filaments that can disrupt vesicular trafficking and cause synaptic loss. Rods are a brain pathology in human AD and mouse models of AD and ADRD. Eliminating rods is the focus of this paper. One pathway for rod formation is triggered in ~20% of rodent hippocampal neurons by disease-related factors (e.g., soluble oligomers of Amyloid-β (Aβ)) and requires cellular prion protein (PrPC), active NADPH oxidase (NOX), and cytokine/chemokine receptors (CCRs). FDA-approved antagonists of CXCR4 and CCR5 inhibit Aβ-induced rods in both rodent and human neurons with effective concentrations for 50% rod reduction (EC50) of 1–10 nM. Remarkably, two D-amino acid receptor-active peptides (RAP-103 and RAP-310) inhibit Aβ-induced rods with an EC50 of ~1 pM in mouse neurons and ~0.1 pM in human neurons. These peptides are analogs of D-Ala-Peptide T-Amide (DAPTA) and share a pentapeptide sequence (TTNYT) antagonistic to several CCR-dependent responses. RAP-103 does not inhibit neuritogenesis or outgrowth even at 1 µM, >106-fold above its EC50. N-terminal methylation, or D-Thr to D-Ser substitution, decreases the rod-inhibiting potency of RAP-103 by 103-fold, suggesting high target specificity. Neither RAP peptide inhibits neuronal rod formation induced by excitotoxic glutamate, but both inhibit rods induced in human neurons by several PrPC/NOX pathway activators (Aβ, HIV-gp120 protein, and IL-6). Significantly, RAP-103 completely protects against Aβ-induced loss of mature and developing synapses and, at 0.1 nM, reverses rods in both rodent and human neurons (T½ ~ 3 h) even in the continuous presence of Aβ. Thus, this orally available, brain-permeable peptide should be highly effective in reducing rod pathology in multifactorial neurological diseases with mixed proteinopathies acting through PrPC/NOX. Full article
(This article belongs to the Special Issue New Perspectives on Neuronal Cytoskeletal Dysregulation in Health and Disease)
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25 pages, 15626 KiB  
Article
Characterization of a Human Neuronal Culture System for the Study of Cofilin–Actin Rod Pathology
by Lubna H. Tahtamouni, Sydney A. Alderfer, Thomas B. Kuhn, Laurie S. Minamide, Soham Chanda, Michael R. Ruff and James R. Bamburg
Biomedicines 2023, 11(11), 2942; https://doi.org/10.3390/biomedicines11112942 - 31 Oct 2023
Cited by 1 | Viewed by 1498
Abstract
Cofilactin rod pathology, which can initiate synapse loss, has been extensively studied in rodent neurons, hippocampal slices, and in vivo mouse models of human neurodegenerative diseases such as Alzheimer’s disease (AD). In these systems, rod formation induced by disease-associated factors, such as soluble [...] Read more.
Cofilactin rod pathology, which can initiate synapse loss, has been extensively studied in rodent neurons, hippocampal slices, and in vivo mouse models of human neurodegenerative diseases such as Alzheimer’s disease (AD). In these systems, rod formation induced by disease-associated factors, such as soluble oligomers of Amyloid-β (Aβ) in AD, utilizes a pathway requiring cellular prion protein (PrPC), NADPH oxidase (NOX), and cytokine/chemokine receptors (CCR5 and/or CXCR4). However, rod pathways have not been systematically assessed in a human neuronal model. Here, we characterize glutamatergic neurons differentiated from human-induced pluripotent stem cells (iPSCs) for the formation of rods in response to activators of the PrPC-dependent pathway. Optimization of substratum, cell density, and use of glial-conditioned medium yielded a robust system for studying the development of Aβ-induced rods in the absence of glia, suggesting a cell-autonomous pathway. Rod induction in younger neurons requires ectopic expression of PrPC, but this dependency disappears by Day 55. The quantification of proteins within the rod-inducing pathway suggests that increased PrPC and CXCR4 expression may be factors in the doubling of the rod response to Aβ between Days 35 and 55. FDA-approved antagonists to CXCR4 and CCR5 inhibit the rod response. Rods were predominantly observed in dendrites, although severe cytoskeletal disruptions prevented the assignment of over 40% of the rods to either an axon or dendrite. In the absence of glia, a condition in which rods are more readily observed, neurons mature and fire action potentials but do not form functional synapses. However, PSD95-containing dendritic spines associate with axonal regions of pre-synaptic vesicles containing the glutamate transporter, VGLUT1. Thus, our results identified stem cell-derived neurons as a robust model for studying cofilactin rod formation in a human cellular environment and for developing effective therapeutic strategies for the treatment of dementias arising from multiple proteinopathies with different rod initiators. Full article
(This article belongs to the Special Issue New Perspectives on Neuronal Cytoskeletal Dysregulation in Health and Disease)
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