Cofilin and Neurodegeneration: New Functions for an Old but Gold Protein

Lapeña-Luzón, Tamara; Rodríguez, Laura R.; Beltran-Beltran, Vicent; Benetó, Noelia; Pallardó, Federico V.; González-Cabo, Pilar

doi:10.3390/brainsci11070954

Cited by 7 publications

(7 citation statements)

References 73 publications

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“…However, there was no change in the level of total NF-κB. These findings are in agreement with other reports that suggest during a neuroinflammatory response, cofilin might intervene and promote the cytoskeleton dynamics of microglia and change its morphology into the activated ameboid phenotype [ 35 , 39 ].…”

Section: Discussionsupporting

confidence: 92%

“…Cofilin is expressed in all cell types, and disturbance of cofilin dynamics has been involved in the pathology of many neurodegenerative disorders [ 35 ]. Cofilin is regulated by phosphatases such as SSH-1 that are activated in response to stress signals, such as ROS accumulation and ATP reduction, leading to cofilin dephosphorylation and activation [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Cofilin Inhibitor Protects against Traumatic Brain Injury-Induced Oxidative Stress and Neuroinflammation

Bahader

James

Almarghalani

et al. 2023

Biology

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Microglial activation and failure of the antioxidant defense mechanisms are major hallmarks in different brain injuries, particularly traumatic brain injury (TBI). Cofilin is a cytoskeleton-associated protein involved in actin binding and severing. In our previous studies, we identified the putative role of cofilin in mediating microglial activation and apoptosis in ischemic and hemorrhagic conditions. Others have highlighted the involvement of cofilin in ROS production and the resultant neuronal death; however, more studies are needed to delineate the role of cofilin in oxidative stress conditions. The present study aims to investigate the cellular and molecular effects of cofilin in TBI using both in vitro and in vivo models as well as the first-in-class small-molecule cofilin inhibitor (CI). An in vitro H2O2-induced oxidative stress model was used in two different types of cells, human neuroblastoma (SH-SY5Y) and microglia (HMC3), along with an in vivo controlled cortical impact model of TBI. Our results show that treatment with H2O2 increases the expression of cofilin and slingshot-1 (SSH-1), an upstream regulator of cofilin, in microglial cells, which was significantly reduced in the CI-treated group. Cofilin inhibition significantly attenuated H2O2-induced microglial activation by reducing the release of proinflammatory mediators. Furthermore, we demonstrate that CI protects against H2O2-induced ROS accumulation and neuronal cytotoxicity, activates the AKT signaling pathway by increasing its phosphorylation, and modulates mitochondrial-related apoptogenic factors. The expression of NF-E2-related factor 2 (Nrf2) and its associated antioxidant enzymes were also increased in CI-treated SY-SY5Y. In the mice model of TBI, CI significantly activated the Nrf2 and reduced the expression of oxidative/nitrosative stress markers at the protein and gene levels. Together, our data suggest that cofilin inhibition provides a neuroprotective effect in in vitro and in vivo TBI mice models by inhibiting oxidative stress and inflammatory responses, the pivotal mechanisms involved in TBI-induced brain damage.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Cofilin Inhibitor Protects against Traumatic Brain Injury-Induced Oxidative Stress and Neuroinflammation

Bahader

James

Almarghalani

et al. 2023

Biology

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“…This process could be mediated by the interaction of cofilin with Drp1 (Hu et al, 2020), although the binding of cofilin to G-actin seems enough to induce its mitochondrial translocation (Rehklau et al, 2012). Under oxidative stress, oxidized cofilin is also translocated to the mitochondria, promoting mitochondrial fission and triggering the release of cytochrome c leading to apoptosis (Klamt et al, 2009;Lapeña-Luzón et al, 2021). Other relevant ABPs of the Gelsolin protein superfamily, like gelsolin itself and villin, modulate apoptosis induction in the gastrointestinal epithelium (Wang et al, 2012;Roy et al, 2018).…”

Section: Actin Cytoskeleton On Apoptosismentioning

confidence: 99%

Regulation of Mitochondrial Function by the Actin Cytoskeleton

Illescas¹,

Peñas²,

Arenas³

et al. 2021

Front. Cell Dev. Biol.

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The regulatory role of actin cytoskeleton on mitochondrial function is a growing research field, but the underlying molecular mechanisms remain poorly understood. Specific actin-binding proteins (ABPs), such as Gelsolin, have also been shown to participate in the pathophysiology of mitochondrial OXPHOS disorders through yet to be defined mechanisms. In this mini-review, we will summarize the experimental evidence supporting the fundamental roles of actin cytoskeleton and ABPs on mitochondrial trafficking, dynamics, biogenesis, metabolism and apoptosis, with a particular focus on Gelsolin involvement in mitochondrial disorders. The functional interplay between the actin cytoskeleton, ABPs and mitochondrial membranes for the regulation of cellular homeostasis thus emerges as a new exciting field for future research and therapeutic approaches.

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“…Cofilin activation leads to axonal damage by promoting actin filament severing and destabilization [64,65]. Cofilin dysregulation has also been explored in various other neurodegenerative conditions, including frontotemporal dementia, multiple sclerosis, and prion diseases, suggesting its potential as a common pathological mechanism [4,[66][67][68][69].…”

Section: Cofilin In Neurodegenerationmentioning

confidence: 99%

“…Despite their distinct etiologies, these conditions share common underlying cellular and molecular mechanisms contributing to neuronal dysfunction and demise [3]. In this era of intensive neurodegeneration research, cofilin protein has emerged as one of the essential players in the intricate web of neuronal homeostasis and dysfunction [4]. Cofilin, a highly conserved actin-binding protein, has garnered significant attention for its pivotal role in modulating cytoskeletal dynamics, cell motility, and synaptic plasticity [5,6].…”

Section: Introductionmentioning

confidence: 99%

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

Shehjar,

Almarghalani,

Mahajan

et al. 2024

Cells

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

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Cofilin and Neurodegeneration: New Functions for an Old but Gold Protein

Cited by 7 publications

References 73 publications

Cofilin Inhibitor Protects against Traumatic Brain Injury-Induced Oxidative Stress and Neuroinflammation

Cofilin Inhibitor Protects against Traumatic Brain Injury-Induced Oxidative Stress and Neuroinflammation

Regulation of Mitochondrial Function by the Actin Cytoskeleton

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

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