Cofilin Aggregation Blocks Intracellular Trafficking and Induces Synaptic Loss in Hippocampal Neurons
Open accessAbstract
Cofilin is an actin-binding protein and a major actin depolymerization factor in the central nervous system (CNS). Cofilin-actin aggregates are associated with neurodegenerative disorders, but how cofilin-actin aggregation induces pathological effects in the CNS remains unclear. Here, we demonstrated that cofilin rods disrupted dendritic microtubule integrity in rat hippocampal cultures. Long term time-lapse imaging revealed that cofilin rods block intracellular trafficking of both mitochondria and early endosomes. Importantly, cofilin rod formation induced a significant loss of SV2 and PSD-95 puncta as well as dendritic spines. Cofilin rods also impaired local glutamate receptor responses. We discovered an inverse relationship between the number of synaptic events and the accumulation of cofilin rods in dendrites. We also detected cofilin rods in aging rat brains in vivo. These results suggest that cofilin aggregation may contribute to neurodegeneration and brain aging by blocking intracellular trafficking and inducing synaptic loss.
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Formation of cofilin-actin rods in distal dendrites is detrimental for synapses.
“Formation of cofilin–actin rods in distal dendrites is detrimental for synapses [7, 19] and cofilin–actin rod pathology has been observed in the brains of post-mortem AD patients [101] and in animal models of AD [7].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [19]
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Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2
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- Authors
- Cichon, J., Sun, C., Chen, B., Jiang, M., Chen, X. A., Sun, Y., Wang, Y., & Chen, G.
- Affiliations
- Pennsylvania State University (US)
- Fudan University (CN)
- Corresponding author
- Wang, Yun
- Chen, Gong
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 287
- Issue
- 6
- Pages
- 3919-3929
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3281697
- OpenAlex
- W2132485762
- Cited by
- 95
- References
- 2
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 5 · 2022: 2 · 2021: 6 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 7 · 2015: 7 · 2014: 5 · 2013: 7 · 2012: 4
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH083911, MH083911)
- National Institute of Neurological Disorders and Stroke (R21NS054858, NS054858)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cofilin, actin depolymerization, hippocampal neurons, dendritic microtubules, mitochondrial trafficking, synaptic loss, dendritic spines, SV2, PSD-95, brain aging, neurodegeneration, intracellular trafficking
- MeSH terms
- Aging, Animals, Biological Transport, Active, Cells, Cultured, Dendrites, Hippocampus, Humans, Nerve Tissue Proteins, Synapses, Neurodegenerative Diseases, Multiprotein Complexes, Actin Depolymerizing Factors, Rats
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