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WWC1/2 regulate spinogenesis and cognition in mice by stabilizing AMOT
Runyi Cao1, Rui Zhu1, Zhao Sha1
1Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
WW C1 proteins regulate learning and memory by stabilizing angiomotin (AMOT) proteins, which is crucial for neuronal function. This discovery sheds light on neurodegenerative disease mechanisms.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- WWC1 is implicated in learning and memory, with its genetic variations linked to neurodegenerative diseases like Alzheimer's.
- The precise molecular mechanisms by which WWC1 influences neuronal function remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanism of WWC1 in regulating neuronal function.
- To investigate the interaction between WWC proteins and angiomotin (AMOT) family proteins (Motins).
Main Methods:
- Investigated the binding of WWC1 and its paralogs (WWC2/3) to Motins.
- Utilized gene deletion in cell types and neuron-specific deletion in mice.
- Assessed protein levels, dendritic spine density, and cognitive functions.
- Employed ectopic expression of AMOT for rescue experiments.
Main Results:
- WWC1/2/3 proteins directly bind to Motins and recruit USP9X for deubiquitination and stabilization.
- Deletion of WWC genes reduces Motin protein levels.
- Neuron-specific deletion of Wwc1/2 in mice decreased Motin expression, reduced dendritic spine density, and impaired cognitive functions.
- Ectopic AMOT expression partially rescued neuronal phenotypes.
Conclusions:
- WWC proteins are critical regulators of Motin protein stability.
- WWC proteins modulate spinogenesis and cognitive functions, including learning and memory, partly via regulating Motin stability.
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