{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:56:15Z","timestamp":1788328575696,"version":"build-2803163510"},"reference-count":154,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke of the National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS112642"],"award-info":[{"award-number":["R01NS112642"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>This comprehensive review explores the complex role of cofilin, an actin-binding protein, across various neurodegenerative diseases (Alzheimer\u2019s, Parkinson\u2019s, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington\u2019s) and stroke. Cofilin is an essential protein in cytoskeletal dynamics, and any dysregulation could lead to potentially serious complications. Cofilin\u2019s involvement is underscored by its impact on pathological hallmarks like A\u03b2 plaques and \u03b1-synuclein aggregates, triggering synaptic dysfunction, dendritic spine loss, and impaired neuronal plasticity, leading to cognitive decline. In Parkinson\u2019s disease, cofilin collaborates with \u03b1-synuclein, exacerbating neurotoxicity and impairing mitochondrial and axonal function. ALS and frontotemporal dementia showcase cofilin\u2019s association with genetic factors like C9ORF72, affecting actin dynamics and contributing to neurotoxicity. Huntington\u2019s disease brings cofilin into focus by impairing microglial migration and influencing synaptic plasticity through AMPA receptor regulation. Alzheimer\u2019s, Parkinson\u2019s, 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.<\/jats:p>","DOI":"10.3390\/cells13020188","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T06:41:22Z","timestamp":1705560082000},"page":"188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Multifaceted Role of Cofilin in Neurodegeneration and Stroke: Insights into Pathogenesis and Targeting as a Therapy"],"prefix":"10.3390","volume":"13","author":[{"given":"Faheem","family":"Shehjar","sequence":"first","affiliation":[{"name":"Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniyah A.","family":"Almarghalani","sequence":"additional","affiliation":[{"name":"Stroke Research Unit, Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reetika","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed A.-M.","family":"Hasan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8977-1618","authenticated-orcid":false,"given":"Zahoor A.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA"},{"name":"Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"883358","DOI":"10.3389\/fnmol.2022.883358","article-title":"Animal Models of Neurodegenerative Disease: Recent Advances in Fly Highlight Innovative Approaches to Drug Discovery","volume":"15","author":"Tello","year":"2022","journal-title":"Front. 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