Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Cells, Journal Year: 2021, Volume and Issue: 10(10), P. 2726 - 2726

Published: Oct. 12, 2021

Proteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and essential regulators dynamics function. Mammalian neurons express cofilin-1 as major isoform, but ADF cofilin-2 also expressed. All isoforms bind preferentially cooperatively along ADP-subunits in F-actin, affecting filament helical rotation, when either alone or enhanced by other proteins, promotes severing subunit turnover. Although self-regulating cofilin-mediated can drive motility without post-translational regulation, cells utilize many mechanisms to locally control cofilin, including cooperation/competition with proteins. Newly identified modifications function independent from well-established phosphorylation serine 3 provide unexplored avenues for isoform specific regulation. Cofilin modulates transport nucleus well organization associated mitochondrial fission mitophagy. Under neuronal stress conditions, cofilin-saturated F-actin fragments undergo oxidative cross-linking bundle together form cofilin-actin rods. Rods abundance within around brain ischemic lesions be rapidly induced neurites most hippocampal cortical through energy depletion glutamate-induced excitotoxicity. In ~20% rodent neurons, rods more slowly a receptor-mediated process triggered factors intimately connected disease-related dementias, e.g., amyloid-β Alzheimer’s disease. This rod-inducing pathway requires cellular prion protein, NADPH oxidase, G-protein coupled receptors, CXCR4 CCR5. Here, we will review aspects cofilin regulation its contribution synaptic loss pathology neurodegenerative diseases.

Language: Английский

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Understanding the physical basis of memory: Molecular mechanisms of the engram

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(5), P. 101866 - 101866

Published: March 26, 2022

Memory, defined as the storage and use of learned information in brain, is necessary to modulate behavior critical for animals adapt their environments survive. Despite being a cornerstone brain function, questions surrounding molecular cellular mechanisms how encoded, stored, recalled remain largely unanswered. One widely held theory that an engram formed by group neurons are active during learning, which undergoes biochemical physical changes store stable state, later reactivated recall memory. In past decade, development labeling methodologies has proven useful investigate biology memory at levels. Engram technology allows study individual memories associated with particular experiences evolution over time, enough experimental resolution discriminate between different processes: learning (encoding), consolidation (the passage from short-term long-term memories), maintenance brain). Here, we review current understanding formation level focusing on insights provided using technology.

Language: Английский

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Actin Cytoskeleton at the Synapse: An Alzheimer's Disease Perspective

Cytoskeleton, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

ABSTRACT Actin, a ubiquitous and highly conserved cytoskeletal protein, plays pivotal role in various cellular functions such as structural support, facilitating cell motility, contributing to the dynamic processes of synaptic function. Apart from its established inducing morphological changes, recent developments field indicate an active involvement actin modulating both structure function pre‐ postsynaptic terminals. Within presynapse, it is involved organization trafficking vesicles, neurotransmitter release. In postsynapse, dynamically modulates dendritic spines, influencing density anchoring receptors. addition, interplay at synapse underscores essential regulating neural communication. This review strives offer comprehensive overview advancements understanding multifaceted cytoskeleton functions. By emphasizing aberrant regulation, we aim provide valuable insights into underlying mechanisms Alzheimer's disease pathophysiology.

Language: Английский

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Rho Signaling in Synaptic Plasticity, Memory, and Brain Disorders

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Oct. 4, 2021

Memory impairments are associated with many brain disorders such as autism, Alzheimer's disease, and depression. Forming memories involves modifications of synaptic transmission spine morphology. The Rho family small GTPases key regulators plasticity by affecting various downstream molecules to remodel the actin cytoskeleton. In this paper, we will review recent studies on roles proteins in regulation hippocampal long-term potentiation (LTP) depression (LTD), most extensively studied forms widely regarded cellular mechanisms for learning memory. We also discuss involvement signaling morphology, structural basis memory formation. Finally, association between abnormalities function. It is expected that studying at synapse contribute understanding how formed disrupted diseases.

Language: Английский

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LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases

Cells, Journal Year: 2021, Volume and Issue: 10(8), P. 2079 - 2079

Published: Aug. 13, 2021

Learning and memory require structural functional modifications of synaptic connections, deficits are believed to underlie many brain disorders. The LIM-domain-containing protein kinases (LIMK1 LIMK2) key regulators the actin cytoskeleton by affecting actin-binding protein, cofilin. In addition, LIMK1 is implicated in regulation gene expression interacting with cAMP-response element-binding protein. Accumulating evidence indicates that LIMKs critically involved function dysfunction. this paper, we will review studies on roles underlying mechanisms long-term potentiation (LTP) depression (LTD), most extensively studied forms long-lasting plasticity widely regarded as cellular learning memory. We also discuss involvement dendritic spine, basis plasticity, formation. Finally, recent progress investigations neurological mental disorders, including Alzheimer's, Parkinson's, Williams-Beuren syndrome, schizophrenia, autism spectrum

Language: Английский

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Cytoskeletal dysregulation and neurodegenerative disease: Formation, monitoring, and inhibition of cofilin-actin rods

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Sept. 22, 2022

The presence of atypical cytoskeletal dynamics, structures, and associated morphologies is a common theme uniting numerous diseases developmental disorders. In particular, dysregulation cellular feature Alzheimer’s disease, Parkinson’s Huntington’s disease. While the activators inhibitors present complexities for characterizing these elements as byproducts or initiators disease state, it increasingly clear that better understanding anomalies critical advancing state knowledge plan therapeutic attack. this review, we focus on hallmarks are with cofilin-linked actin regulation, particular emphasis formation, monitoring, inhibition cofilin-actin rods. We also review actin-associated proteins other than cofilin links to cytoskeleton-associated neurodegenerative processes, recognizing rods comprise one strand vast web interactions occur result dysregulation. Our aim current perspective dysregulation, connecting recent developments in our emerging strategies biosensing biomimicry will help shape future directions field.

Language: Английский

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PAK4 in cancer development: Emerging player and therapeutic opportunities

Cancer Letters, Journal Year: 2022, Volume and Issue: 545, P. 215813 - 215813

Published: July 4, 2022

Language: Английский

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The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 188 - 188

Published: Jan. 18, 2024

This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer’s, Parkinson’s, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington’s) and stroke. Cofilin is essential protein in cytoskeletal dynamics, any dysregulation could lead to potentially serious complications. Cofilin’s involvement underscored by its impact on pathological hallmarks like Aβ plaques α-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, impaired neuronal plasticity, leading cognitive decline. In Parkinson’s disease, cofilin collaborates with α-synuclein, exacerbating neurotoxicity impairing mitochondrial axonal function. ALS frontotemporal dementia showcase cofilin’s association genetic factors C9ORF72, affecting actin dynamics contributing neurotoxicity. Huntington’s disease brings into focus microglial migration influencing plasticity through AMPA receptor regulation. Alzheimer’s, schizophrenia exhibit 14-3-3 proteins as a shared mechanism. case stroke, takes center stage, mediating cell death. Notably, there potential overlap pathologies diseases. this context, referencing dysfunction provide valuable insights common associated aforementioned conditions. Moreover, promising therapeutic interventions, including inhibitors gene therapy, demonstrating efficacy preclinical models. Challenges inhibitor development, brain delivery, tissue/cell specificity, long-term safety are acknowledged, emphasizing need for precision drug therapy. The call action involves collaborative research, biomarker identification, advancing translational efforts. emerges pivotal player, offering target. However, unraveling complexities requires concerted multidisciplinary efforts nuanced effective interventions intricate landscape presenting hopeful avenue improved patient care.

Language: Английский

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Actin Cytoskeleton Role in the Maintenance of Neuronal Morphology and Long-Term Memory

Cells, Journal Year: 2021, Volume and Issue: 10(7), P. 1795 - 1795

Published: July 15, 2021

Evidence indicates that long-term memory formation creates long-lasting changes in neuronal morphology within a specific network forms the trace. Dendritic spines, which include most of excitatory synapses neurons, are formed or eliminated by learning. These may be and correlate with strength. Moreover, learning-induced existing spines can also contribute to underlies memory. Altering after consolidation erase observations strongly suggest modifications constitute synaptic connectivity form stabilization this maintains The elimination other finer morphological mediated actin cytoskeleton. cytoskeleton networks spine support its structure. Therefore, it is believed mediates morphogenesis induced Any learning require preservation stabilize new However, highly dynamic, turnover regulatory proteins determine structure relatively fast. Molecular models, suggested here, describe ways overcome dynamic nature fast protein an enduring stability models based on concentrations scaffold ability for recurring rebuilding spine. persistence maintenance

Language: Английский

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The penalty of stress ‐ Epichaperomes negatively reshaping the brain in neurodegenerative disorders

Journal of Neurochemistry, Journal Year: 2021, Volume and Issue: 159(6), P. 958 - 979

Published: Oct. 19, 2021

Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, an effector change organismal homeostasis the response generated when brain perceives potential threat. Herein, we discuss nuanced granular view whereby variety genotoxic environmental stressors, including aging, genetic risk factors, exposures, age- lifestyle-related changes, act as direct insults cellular, opposed organismal, homeostasis. These two concepts how impact are not mutually exclusive. We maladaptive stressor-induced changes protein connectivity through epichaperomes, disease-associated pathologic scaffolds composed tightly bound chaperones, co-chaperones, other intracellular functionality altering phenotypes, that turn disrupt remodel networks ranging from intercellular connectome levels. provide evidence-based on these stressor phenotype unique precision medicine opportunities for diagnostic therapeutic development, especially context neurodegenerative disorders Alzheimer's disease where treatment options currently limited.

Language: Английский

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