Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration
Proteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and are essential regulators of actin dynamics and function. Mammalian neurons express cofilin-1 as the major isoform, but ADF and cofilin-2 are also expressed. All isoforms bind preferentially and coope...
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MDPI AG
2021-10-01
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| author | James R. Bamburg Laurie S. Minamide O’Neil Wiggan Lubna H. Tahtamouni Thomas B. Kuhn |
| author_facet | James R. Bamburg Laurie S. Minamide O’Neil Wiggan Lubna H. Tahtamouni Thomas B. Kuhn |
| author_sort | James R. Bamburg |
| collection | DOAJ |
| description | Proteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and are essential regulators of actin dynamics and function. Mammalian neurons express cofilin-1 as the major isoform, but ADF and cofilin-2 are also expressed. All isoforms bind preferentially and cooperatively along ADP-subunits in F-actin, affecting the filament helical rotation, and when either alone or when enhanced by other proteins, promotes filament severing and subunit turnover. Although self-regulating cofilin-mediated actin dynamics can drive motility without post-translational regulation, cells utilize many mechanisms to locally control cofilin, including cooperation/competition with other proteins. Newly identified post-translational modifications function with or are independent from the well-established phosphorylation of serine 3 and provide unexplored avenues for isoform specific regulation. Cofilin modulates actin transport and function in the nucleus as well as actin organization associated with mitochondrial fission and mitophagy. Under neuronal stress conditions, cofilin-saturated F-actin fragments can undergo oxidative cross-linking and bundle together to form cofilin-actin rods. Rods form in abundance within neurons around brain ischemic lesions and can be rapidly induced in neurites of most hippocampal and cortical neurons through energy depletion or glutamate-induced excitotoxicity. In ~20% of rodent hippocampal neurons, rods form more slowly in a receptor-mediated process triggered by factors intimately connected to disease-related dementias, e.g., amyloid-β in Alzheimer’s disease. This rod-inducing pathway requires a cellular prion protein, NADPH oxidase, and G-protein coupled receptors, e.g., CXCR4 and CCR5. Here, we will review many aspects of cofilin regulation and its contribution to synaptic loss and pathology of neurodegenerative diseases. |
| first_indexed | 2024-03-10T06:39:28Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-10T06:39:28Z |
| publishDate | 2021-10-01 |
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| series | Cells |
| spelling | doaj.art-5fd5f401e4a24a16a2483cabf110bfca2023-11-22T17:48:11ZengMDPI AGCells2073-44092021-10-011010272610.3390/cells10102726Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and DegenerationJames R. Bamburg0Laurie S. Minamide1O’Neil Wiggan2Lubna H. Tahtamouni3Thomas B. Kuhn4Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USADepartment of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USADepartment of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USADepartment of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USADepartment of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USAProteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and are essential regulators of actin dynamics and function. Mammalian neurons express cofilin-1 as the major isoform, but ADF and cofilin-2 are also expressed. All isoforms bind preferentially and cooperatively along ADP-subunits in F-actin, affecting the filament helical rotation, and when either alone or when enhanced by other proteins, promotes filament severing and subunit turnover. Although self-regulating cofilin-mediated actin dynamics can drive motility without post-translational regulation, cells utilize many mechanisms to locally control cofilin, including cooperation/competition with other proteins. Newly identified post-translational modifications function with or are independent from the well-established phosphorylation of serine 3 and provide unexplored avenues for isoform specific regulation. Cofilin modulates actin transport and function in the nucleus as well as actin organization associated with mitochondrial fission and mitophagy. Under neuronal stress conditions, cofilin-saturated F-actin fragments can undergo oxidative cross-linking and bundle together to form cofilin-actin rods. Rods form in abundance within neurons around brain ischemic lesions and can be rapidly induced in neurites of most hippocampal and cortical neurons through energy depletion or glutamate-induced excitotoxicity. In ~20% of rodent hippocampal neurons, rods form more slowly in a receptor-mediated process triggered by factors intimately connected to disease-related dementias, e.g., amyloid-β in Alzheimer’s disease. This rod-inducing pathway requires a cellular prion protein, NADPH oxidase, and G-protein coupled receptors, e.g., CXCR4 and CCR5. Here, we will review many aspects of cofilin regulation and its contribution to synaptic loss and pathology of neurodegenerative diseases.https://www.mdpi.com/2073-4409/10/10/2726cofilinactin dynamicspost-translational modificationsneuritogenesisneurodegenerative diseasescofilin-actin rods |
| spellingShingle | James R. Bamburg Laurie S. Minamide O’Neil Wiggan Lubna H. Tahtamouni Thomas B. Kuhn Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration Cells cofilin actin dynamics post-translational modifications neuritogenesis neurodegenerative diseases cofilin-actin rods |
| title | Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration |
| title_full | Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration |
| title_fullStr | Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration |
| title_full_unstemmed | Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration |
| title_short | Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration |
| title_sort | cofilin and actin dynamics multiple modes of regulation and their impacts in neuronal development and degeneration |
| topic | cofilin actin dynamics post-translational modifications neuritogenesis neurodegenerative diseases cofilin-actin rods |
| url | https://www.mdpi.com/2073-4409/10/10/2726 |
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