A variety of missense mutations and a stop mutation in the gene coding for transmembrane protein 240 (TMEM240) have been reported to be the causative mutations of spinocerebellar ataxia 21 (SCA21). We aimed to investigate the expression of TMEM240 protein in mouse brain at the tissue, cellular, and subcellular levels. Immunofluorescence labeling showed TMEM240 to be expressed in various areas of the brain, with the highest levels in the hippocampus, isocortex, and cerebellum. In the cerebellum, TMEM240 was detected in the deep nuclei and the cerebellar cortex. The protein was expressed in all three layers of the cortex and various cerebellar neurons. TMEM240 was localized to climbing, mossy, and parallel fiber afferents projecting to Purkinje cells, as shown by co-immunostaining with VGLUT1 and VGLUT2. Co-immunostaining with synaptophysin, post-synaptic fractionation, and confirmatory electron microscopy showed TMEM240 to be localized to the post-synaptic side of synapses near the Purkinje-cell soma. Similar results were obtained in human cerebellar sections. These data suggest that TMEM240 may be involved in the organization of the cerebellar network, particularly in synaptic inputs converging on Purkinje cells. This study is the first to describe TMEM240 expression in the normal mouse brain.
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Hersheson J, Haworth A, Houlden H. The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics. Hum Mutat. 2012;33:1324–32.
Delplanque J, Devos D, Vuillaume I, De Becdelievre A, Vangelder E, Maurage CA, et al. Slowly progressive spinocerebellar ataxia with extrapyramidal signs and mild cognitive impairment (SCA21). Cerebellum. 2008;7:179–83.
Delplanque J, Devos D, Huin V, Genet A, Sand O, Moreau C, et al. TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment. Brain. 2014;137:2657–63.
Zeng S, Zeng J, He M, Zeng X, Zhou Y, Liu Z et al. Spinocerebellar ataxia type 21 exists in the Chinese Han population. Scientific Reports [Internet]. 2016 [cited 2019 Dec 17];6. Available from: http://www.nature.com/articles/srep19897.
Yahikozawa H, Miyatake S, Sakai T, Uehara T, Yamada M, Hanyu N, et al. A Japanese family of spinocerebellar ataxia type 21: clinical and neuropathological studies. Cerebellum. 2018;17:525–30.
Traschütz A, van Gaalen J, Oosterloo M, Vreeburg M, Kamsteeg E-J, Deininger N, et al. The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature. Parkinsonism Relat Disord. 2019;62:215–20.
Trinidad JC, Barkan DT, Gulledge BF, Thalhammer A, Sali A, Schoepfer R, et al. Global identification and characterization of both O-GlcNAcylation and phosphorylation at the murine synapse. Mol Cell Proteomics. 2012;11:215–29.
Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489:391–9.
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419–9.
Koziol LF, Budding D, Andreasen N, D’Arrigo S, Bulgheroni S, Imamizu H, et al. Consensus paper: the cerebellum’s role in movement and cognition. Cerebellum. 2014;13:151–77.
Mariën P, Ackermann H, Adamaszek M, Barwood CHS, Beaton A, Desmond J et al. Consensus paper: language and the cerebellum: an ongoing enigma. The cerebellum [Internet]. 2013 [cited 2019 Dec 17]; Available from: http://link.springer.com/10.1007/s12311-013-0540-5.
Schmahmann JD, Sherman JC. Cerebellar cognitive affective syndrome. Int Rev Neurobiol. 1997;41:433–40.
Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121(Pt 4):561–79.
Larsell O. The morphogenesis and adult pattern of the lobules and fissures of the cerebellum of the white rat. J Comp Neurol. 1952;97:281–356.
Eccles JC, Ito M, Szentágothai J. Architectural design of the cerebellar cortex. The cerebellum as a neuronal machine [Internet]. Berlin, Heidelberg: Springer Berlin Heidelberg; 1967 [cited 2019 Dec 17]. p. 195–204. Available from: http://link.springer.com/10.1007/978-3-662-13147-3_12.
Sillitoe RV, Joyner AL. Morphology, molecular codes, and circuitry produce the three-dimensional complexity of the cerebellum. Annu Rev Cell Dev Biol. 2007;23:549–77.
Beckinghausen J, Sillitoe RV. Insights into cerebellar development and connectivity. Neurosci Lett. 2019;688:2–13.
Seki T, Sato M, Kibe Y, Ohta T, Oshima M, Konno A, et al. Lysosomal dysfunction and early glial activation are involved in the pathogenesis of spinocerebellar ataxia type 21 caused by mutant transmembrane protein 240. Neurobiol Dis. 2018;120:34–50.
Schmahmann JD. The cerebellum and cognition. Neurosci Lett. 2019;688:62–75.
Devos D, Schraen-Maschke S, Vuillaume I, Dujardin K, Nazé P, Willoteaux C, et al. Clinical features and genetic analysis of a new form of spinocerebellar ataxia. Neurology. 2001;56:234–8.
Matilla-Dueñas A, Ashizawa T, Brice A, Magri S, McFarland KN, Pandolfo M, et al. Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias. Cerebellum. 2014;13:269–302.
Gebre SA, Reeber SL, Sillitoe RV. Parasagittal compartmentation of cerebellar mossy fibers as revealed by the patterned expression of vesicular glutamate transporters VGLUT1 and VGLUT2. Brain Struct Funct. 2012;217:165–80.
Hioki H, Fujiyama F, Taki K, Tomioka R, Furuta T, Tamamaki N, et al. Differential distribution of vesicular glutamate transporters in the rat cerebellar cortex. Neuroscience. 2003;117:1–6.
Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N. A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron. 2002;35:921–33.
Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology. 2005;65:529–34.
We thank the Lille NeuroBank (CHRU-Lille) for providing the human brain tissue and Nicolas Van Poucke from the Lille Biology and Pathology center. We also thank Dr. Meryem Tardivel and Antonino Bongiovanni from the cellular imagery platform for the confocal microscopy experiments. Finally, we thank Dr. Khalid Hamid El Hachimi (ICM, Paris) for his invaluable advice on interpreting the electron microscopy data.
The research leading to these results was funded by the French government’s LabEx program (“Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease”—DISTALZ), the University of Lille, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Connaître les Syndrômes Cérébelleux (CSC) charity.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted. Experimental protocols were approved by the local animal ethical committee (approval APAFIS#2264-2015101320441671 from CEEA75, Lille, France). Human brains were obtained from the Lille Neurobank (CRB/CIC1403 Biobank, BB-0033-00030, agreement DC-2008-642), which fulfills the criteria of the local laws and regulations on biological resources with donor consent, data protection, and ethical committee review.
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Homa, M., Loyens, A., Eddarkaoui, S. et al. The TMEM240 Protein, Mutated in SCA21, Is Expressed in Purkinje Cells and Synaptic Terminals. Cerebellum 19, 358–369 (2020). https://doi.org/10.1007/s12311-020-01112-y
- Purkinje cell