NALCN – UNC80 Research advances CLIFAHDD and IHPRF Syndrome

Fundación Libellas. September 2020. Newsletter.

https:fundacionlibellas.org

Our understanding of the NALCN protein complex responsible for the CLIFAHDD and IHPRF1&2 syndromes has reached new milestones over the last months. Two recent studies (Ou et al, 2020; Kschonsak et al, 2020) just confirmed the initial finding (Bouasse et al, 2019) that CLIFAHDD and IHPRF1 are due to mutations that alter NALCN function in opposite ways, i.e. through a gain- or a loss-of-function, respectively. Now, researchers must find ways to modulate directly the NALCN function or counterbalance its deficiency. This challenge will undoubtedly benefit from the elucidation of the 3-dimensional NALCN structure by three different groups (Kschonsak et al, 2020; Zhang et al*; Xie et al*), and the identification of a lock that will be a target of choice to find the right keys to close or open it.

The quest for NALCN inhibitors to treat patients with the CLIFAHDD syndrome is particularly relevant since a study conducted in worms provided the first proof-of-concept that dystonia caused by a gain-of-function mutation of NALCN may be corrected in vivo. Moreover, several studies already reported how NALCN function is modulated by extracellular calcium (Lee et al, 2019; Chua et al, 2020), isoflurane (e.g. a volatile anesthetic; Ou et al, 2020), and other chemical compounds (Hahn et al, 2020). The design of future drugs will build on the ground of these pioneer data.

Other studies reported novel mutations of NALCN in patients with the IHPRF1 syndromes (Ope et al, 2020), and a mouse model of the IHPRF2 syndrome linked to UNC-80 dysfunction was developed as well as a mouse model expressing a “green” NALCN protein, which unveiled that UNC-80 impacts on NALCN function by disrupting its neuronal localization (Wie et al, 2020).

Unexpectedly, two other studies revealed that NALCN is also involved well beyond CLIFAHDD and IHPRF1&2 syndromes, in cancer and in neuropathic pain (Iamshanova et al*; Zhang et al*). One may thus expect a growing interest for this once neglected protein. Together with the ability of expressing NALCN in cultured cells and the knowledge of its 3D structure, this will speed up the identification of specific molecules to modulate its function, and the development of novel therapeutic strategies for patients. It is now predictable that major advances will be accomplished within the next years.

                                                                                 Fundación Libellas

*Studies deposited to bioRxiv are not peer-reviewed ones.

References:

Chua HC, Wulf M, Weidling C, Rasmussen LP, Pless SA. The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium. Sci Adv. 2020 Apr 24;6(17):eaaz3154. doi: 10.1126/sciadv.aaz3154.

Hahn S, Kim SW, Um KB, Kim HJ, Park MK. N-benzhydryl quinuclidine compounds are a potent and Src kinase-independent inhibitor of NALCN channels. Br J Pharmacol. 2020 Aug;177(16):3795-3810. doi: 10.1111/bph.15104.

Oksana Iamshanova, Dmitri Gordienko, Antoine Folcher, Alexandre Bokhobza, George Shapovalov, Pascal Mariot, Laurent Allart, Emilie Desruelles, Corentin Spriet, Raquel Diez, Thibauld Oullier, Séverine Marionneau-Lambot, Lucie Brisson, Sandra Geraci, Hathaichanok Impheng, V’yacheslav Lehen’kyi, Aurelien Haustrate, Adriana Mihalache, Pierre Gosset, Stéphanie Chadet, Stéphanie Lerondel, Stéphanie Retif, Maryline Le Mée, Julien Sobilo, Sébastien Roger, Gaelle Fromont-Hankard, Mustafa Djamgoz, Philippe Clezardin, Arnaud Monteil, Natalia Prevarskaya. Malignant assignment of neuronal Na+ leak channel, NALCN: governor of Ca2+ oscillations-encoded invadopodogenesis. bioRxiv 2020.08.13.249169; doi: https://doi.org/10.1101/2020.08.13.249169

Kasap M, Aamodt EJ, Sagrera CE, Dwyer DS. Novel pharmacological modulation of dystonic phenotypes caused by a gain-of-function mutation in the Na+ leak-current channel. Behav Pharmacol. 2020 Aug;31(5):465-476. doi: 10.1097/FBP.0000000000000526.

Kschonsak M, Chua HC, Noland CL, Weidling C, Clairfeuille T, Bahlke OØ, Ameen AO, Li ZR, Arthur CP, Ciferri C, Pless SA, Payandeh J. Structure of the human sodium leak channel NALCN. Nature. 2020 Jul 22. doi: 10.1038/s41586-020-2570-8.

Lee SY, Vuong TA, Wen X, Jeong HJ, So HK, Kwon I, Kang JS, Cho H. Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells.  Exp Mol Med. 2019 Oct 10;51(10):1-14. doi: 10.1038/s12276-019-0325-0.

Ope O, Bhoj EJ, Nelson B, Li D, Hakonarson H, Sobering AK. A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.  Am J Med Genet A. 2020 Jul 2. doi: 10.1002/ajmg.a.61744.

Ou M, Zhao W, Liu J, Liang P, Huang H, Yu H, Zhu T, Zhou C. The General Anesthetic Isoflurane Bilaterally Modulates Neuronal Excitability. iScience. 2020 Jan 24;23(1):100760. doi: 10.1016/j.isci.2019.100760.

Wie J, Bharthur A, Wolfgang M, Narayanan V, Ramsey K; C4RCD Research Group, Aranda K, Zhang Q, Zhou Y, Ren D. Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex. Nat Commun. 2020 Jul 3;11(1):3351. doi: 10.1038/s41467-020-17105-8.

Jiongfang Xie, Meng Ke, Lizhen Xu, Shiyi Lin, Jiabei Zhang, Fan Yang, Jianping Wu, Zhen Yan. Structure of human sodium leak channel NALCN in complex with FAM155A. bioRxiv 2020.07.24.218958; doi: https://doi.org/10.1101/2020.07.24.218958

Donghang Zhang, Wenling Zhao, Jin Liu, Mengchan Ou, Peng Liang, Jia Li, Yali Chen, Daqing Liao, Siqi Bai, Jiefei Shen, Xiangdong Chen, Han Huang, Cheng Zhou. Sodium leak channel as a therapeutic target for neuronal sensitization in neuropathic pain. bioRxiv 2020.08.17.253534; doi: https://doi.org/10.1101/2020.08.17.253534