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bioRxiv · 10.1101/620708

Ankyrin-G-190 palmitoylation mediates dendrite and spine morphogenesis and is altered in response to lithium

Piguel, N. H.·Yoon, S.·De Simone, F. I.·Sanders, S. S.·Gao, R.·Horan, K. E.·Dionisio, L. E.·Garza, J. C.·Petryshen, T.·Thomas, G. M.·Smith, K. R.·Penzes, P.
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Abstract

AnkG, encoded by the ANK3 gene, is a multifunctional scaffold protein with complex isoform expression: the 480 kDa and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, whereas the 190 kDa isoform (AnkG-190) has an emerging role in the dendritic shaft and spine heads. All isoforms of AnkG undergo palmitoylation, a post-translational modification regulating protein attachment to lipid membranes. However, palmitoylation of AnkG-190 has not been investigated in dendritic spines. The ANK3 gene and altered expression of AnkG proteins are associated with a variety of neuropsychiatric and neurodevelopmental disorders including bipolar disorders and are implicated in the lithium response, a commonly used mood stabilizer for bipolar disorder patients, although the precise mechanisms involved are unknown. Here, we showed that Cys70 palmitoylation stabilizes the localization of AnkG-190 in spine heads and at dendritic plasma membrane nanodomains. Mutation of Cys70 impairs AnkG-190 function in dendritic spines and alters PSD-95 scaffolding. Interestingly, we find that lithium reduces AnkG-190 palmitoylation thereby increasing its mobility in dendritic spines. Finally, we demonstrate that the palmitoyl acyl transferase ZDHHC8, but not ZDHHC5, increases AnkG-190 stability in spine heads and is inhibited by lithium. Together, our data reveal that palmitoylation is critical for AnkG-190 localization and function and a potential ZDDHC8/AnkG-190 mechanism linking AnkG-190 mobility to the neuronal effects of lithium.

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Piguel, N. H., Yoon, S., De Simone, F. I., Sanders, S. S., Gao, R., Horan, K. E., Dionisio, L. E., Garza, J. C., Petryshen, T., Thomas, G. M., Smith, K. R., Penzes, P.. 2019-05-02. Ankyrin-G-190 palmitoylation mediates dendrite and spine morphogenesis and is altered in response to lithium. https://doi.org/10.1101/620708

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