Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 6, Pages 3919-3929Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.301911
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Funding
- National Institutes of Health [NS054858, MH083911]
- National Science Foundation [0821955]
- American Heart Association [0765258U]
- Natural Science Foundation of China [30828014, 31129003, 81171224]
- Ministry of Science and Technology of China [2009CB522000]
- Science and Technology Commission of Shanghai Municipality [09JC1401900]
- Direct For Biological Sciences
- Division Of Integrative Organismal Systems [0821955] Funding Source: National Science Foundation
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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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