Journal
CELL REPORTS
Volume 20, Issue 13, Pages 3071-3084Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.08.100
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Funding
- Scientific Research on Innovation Area (Brain Protein Aging and Dementia Control)
- Mext
- Grants-in-Aid for Scientific Research [15K09310, 26117004, 17H04195] Funding Source: KAKEN
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FUS is an RNA-binding protein associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated intrinsic roles of FUS in synaptic function. However, the mechanism underlying FUS's regulation of synaptic morphology has remained unclear. We found that reduced mature spines after FUS depletion were associated with the internalization of PSD-95 within the dendritic shaft. Mass spectrometry of PSD-95-interacting proteins identified SynGAP, whose expression decreased after FUS depletion. Moreover, FUS and the ELAV-like proteins ELAVL4 and ELAVL1 control SynGAP mRNA stability in a 3'UTR length-dependent manner, resulting in the stable expression of the alternatively spliced SynGAP isoform alpha 2. Finally, abnormal spine maturation and FTLD-like behavioral deficits in FUS-knockout mice were ameliorated by SynGAP alpha 2. Our findings establish an important link between FUS and ELAVL proteins for mRNA stability control and indicate that this mechanism is crucial for the maintenance of synaptic morphology and cognitive function.
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