Palmitoylation-dependent CDKL5-PSD-95 Interaction Regulates Synaptic Targeting of CDKL5 and Dendritic Spine Development

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 May 15

PMID 23671101

Citations 56

Authors

Yong-Chuan Zhu

Dan Li

Lu Wang

Bin Lu

Jing Zheng

Shi-Lin Zhao

Rong Zeng

Zhi-Qi Xiong

Affiliations

Soon will be listed here.

Abstract

The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in severe neurodevelopmental disorders, including some forms of atypical Rett syndrome, but the function and regulation of CDKL5 protein in neurons remain to be elucidated. Here, we show that CDKL5 binds to the scaffolding protein postsynaptic density (PSD)-95, and that this binding promotes the targeting of CDKL5 to excitatory synapses. Interestingly, this binding is not constitutive, but governed by palmitate cycling on PSD-95. Furthermore, pathogenic mutations that truncate the C-terminal tail of CDKL5 diminish its binding to PSD-95 and synaptic accumulation. Importantly, down-regulation of CDKL5 by RNA interference (RNAi) or interference with the CDKL5-PSD-95 interaction inhibits dendritic spine formation and growth. These results demonstrate a critical role of the palmitoylation-dependent CDKL5-PSD-95 interaction in localizing CDKL5 to synapses for normal spine development and suggest that disruption of this interaction by pathogenic mutations may be implicated in the pathogenesis of CDKL5-related disorders.

Citing Articles

A Novel Mouse Model Unveils Protein Deficiency in Truncated CDKL5 Mutations.

Feng X, Zhu Z, Wang H, Zhou H, Liu J, Shen Y Neurosci Bull. 2025; .

PMID: 40042769 DOI: 10.1007/s12264-024-01346-4.

Independent genetic strategies define the scope and limits of CDKL5 deficiency disorder reversal.

Song X, Xia Z, Martinez D, Xu B, Spritzer Z, Zhang Y Cell Rep Med. 2025; 6(2):101926.

PMID: 39855191 PMC: 11866500. DOI: 10.1016/j.xcrm.2024.101926.

Bacterial Production of CDKL5 Catalytic Domain: Insights in Aggregation, Internal Translation and Phosphorylation Patterns.

Colarusso A, Lauro C, Cane L, Cozzolino F, Tutino M Int J Mol Sci. 2024; 25(16).

PMID: 39201578 PMC: 11354467. DOI: 10.3390/ijms25168891.

Novel CDKL5 targets identified in human iPSC-derived neurons.

Massey S, Ang C, Davidson N, Quigley A, Rollo B, Harris A Cell Mol Life Sci. 2024; 81(1):347.

PMID: 39136782 PMC: 11335273. DOI: 10.1007/s00018-024-05389-8.

Distinct palmitoylation of Foxp3 regulates the function of regulatory T cells via palmitoyltransferases.

Zhou B, Zhang M, Ma H, Wang Y, Qiu J, Liu Y Cell Mol Immunol. 2024; 21(7):787-789.

PMID: 38720064 PMC: 11214613. DOI: 10.1038/s41423-024-01166-6.

References

Mumby S . Reversible palmitoylation of signaling proteins. Curr Opin Cell Biol. 1997; 9(2):148-54. DOI: 10.1016/s0955-0674(97)80056-7. View

Kameshita I, Sekiguchi M, Hamasaki D, Sugiyama Y, Hatano N, Suetake I . Cyclin-dependent kinase-like 5 binds and phosphorylates DNA methyltransferase 1. Biochem Biophys Res Commun. 2008; 377(4):1162-7. DOI: 10.1016/j.bbrc.2008.10.113. View

Irie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K . Binding of neuroligins to PSD-95. Science. 1997; 277(5331):1511-5. DOI: 10.1126/science.277.5331.1511. View

Montini E, Andolfi G, Caruso A, Buchner G, Walpole S, Mariani M . Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region. Genomics. 1998; 51(3):427-33. DOI: 10.1006/geno.1998.5391. View

El-Husseini A, Schnell E, Chetkovich D, Nicoll R, Bredt D . PSD-95 involvement in maturation of excitatory synapses. Science. 2000; 290(5495):1364-8. View

Mari F, Azimonti S, Bertani I, Bolognese F, Colombo E, Caselli R . CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum Mol Genet. 2005; 14(14):1935-46. DOI: 10.1093/hmg/ddi198. View

Wang I, Allen M, Goffin D, Zhu X, Fairless A, Brodkin E . Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. Proc Natl Acad Sci U S A. 2012; 109(52):21516-21. PMC: 3535652. DOI: 10.1073/pnas.1216988110. View

Chen Q, Zhu Y, Yu J, Miao S, Zheng J, Xu L . CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling. J Neurosci. 2010; 30(38):12777-86. PMC: 6633570. DOI: 10.1523/JNEUROSCI.1102-10.2010. View

Fukata Y, Fukata M . Protein palmitoylation in neuronal development and synaptic plasticity. Nat Rev Neurosci. 2010; 11(3):161-75. DOI: 10.1038/nrn2788. View

10.

Yoshii A, Murata Y, Kim J, Zhang C, Shokat K, Constantine-Paton M . TrkB and protein kinase Mζ regulate synaptic localization of PSD-95 in developing cortex. J Neurosci. 2011; 31(33):11894-904. PMC: 3158490. DOI: 10.1523/JNEUROSCI.2190-11.2011. View

11.

Kennedy M . The postsynaptic density at glutamatergic synapses. Trends Neurosci. 1997; 20(6):264-8. DOI: 10.1016/s0166-2236(96)01033-8. View

12.

Topinka J, Bredt D . N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron. 1998; 20(1):125-34. DOI: 10.1016/s0896-6273(00)80440-7. View

13.

Ricciardi S, Ungaro F, Hambrock M, Rademacher N, Stefanelli G, Brambilla D . CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol. 2012; 14(9):911-23. PMC: 6485419. DOI: 10.1038/ncb2566. View

14.

Kilstrup-Nielsen C, Rusconi L, La Montanara P, Ciceri D, Bergo A, Bedogni F . What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy. Neural Plast. 2012; 2012:728267. PMC: 3385648. DOI: 10.1155/2012/728267. View

15.

Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V . CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. J Biol Chem. 2008; 283(44):30101-11. PMC: 2662074. DOI: 10.1074/jbc.M804613200. View

16.

Webb Y, Resh M . Inhibition of protein palmitoylation, raft localization, and T cell signaling by 2-bromopalmitate and polyunsaturated fatty acids. J Biol Chem. 2000; 275(1):261-70. DOI: 10.1074/jbc.275.1.261. View

17.

Rao A, Kim E, Sheng M, Craig A . Heterogeneity in the molecular composition of excitatory postsynaptic sites during development of hippocampal neurons in culture. J Neurosci. 1998; 18(4):1217-29. PMC: 6792722. View

18.

Iwanaga T, Tsutsumi R, Noritake J, Fukata Y, Fukata M . Dynamic protein palmitoylation in cellular signaling. Prog Lipid Res. 2009; 48(3-4):117-27. DOI: 10.1016/j.plipres.2009.02.001. View

19.

Brenman J, Chao D, Gee S, McGee A, Craven S, Santillano D . Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell. 1996; 84(5):757-67. DOI: 10.1016/s0092-8674(00)81053-3. View

20.

Craven S, El-Husseini A, Bredt D . Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs. Neuron. 1999; 22(3):497-509. DOI: 10.1016/s0896-6273(00)80705-9. View