Cofilin Aggregation Blocks Intracellular Trafficking and Induces Synaptic Loss in Hippocampal Neurons

• Published in: The Journal of biological chemistry Vol. 287; no. 6; pp. 3919 - 3929
• Main Authors: Cichon, Joseph, Sun, Chicheng, Chen, Ben, Jiang, Min, Chen, Xiangyun Amy, Sun, Yajie, Wang, Yun, Chen, Gong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Actin; Actin Depolymerizing Factors - genetics; Actin Depolymerizing Factors - metabolism; Aging - genetics; Aging - metabolism; Aging - pathology; Alzheimer Disease; Animals; Biological Transport, Active - genetics; Cells, Cultured; Cofilin; Dendrites - metabolism; Dendrites - pathology; Hippocampus - metabolism; Hippocampus - pathology; Humans; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Rats; Synapses; Synapses - genetics; Synapses - metabolism; Synapses - pathology; Trafficking; Cofilin; Alzheimer Disease; Actin; Neurodegeneration; Trafficking; Synapses
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.301911

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. Background: Cofilin rods are associated with Alzheimer disease, but their pathological significance is unclear. Results: Time-lapse imaging revealed that cofilin rods inhibit the movement of mitochondria and early endosomes. Cofilin rods reduce dendritic spines and impair synaptic transmission. Cofilin rods are discovered in senile rat brains. Conclusion: Cofilin rods block intracellular transport and induce synaptic loss. Significance: Our work identifies a signaling pathway underlying neurodegeneration and brain aging.