Leucine-Rich Repeats and Transmembrane Domain 2 Controls Protein Sorting in the Striatal Projection System and Its Deficiency Causes Disturbances in Motor Responses and Monoamine Dynamics

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2022 May 26

PMID 35615067

Authors

Misato Ichise

Kazuto Sakoori

Kei-Ichi Katayama

Naoko Morimura

Kazuyuki Yamada

Hiroki Ozawa

Hayato Matsunaga

Minoru Hatayama

Jun Aruga

Affiliations

Soon will be listed here.

Abstract

The striatum is involved in action selection, and its disturbance can cause movement disorders. Here, we show that leucine-rich repeats and transmembrane domain 2 (Lrtm2) controls protein sorting in striatal projection systems, and its deficiency causes disturbances in monoamine dynamics and behavior. The Lrtm2 protein was broadly detected in the brain, but it was enhanced in the olfactory bulb and dorsal striatum. Immunostaining revealed a strong signal in striatal projection output, including GABAergic presynaptic boutons of the SNr. In subcellular fractionation, Lrtm2 was abundantly recovered in the synaptic plasma membrane fraction, synaptic vesicle fraction, and microsome fraction. Lrtm2 KO mice exhibited altered motor responses in both voluntary explorations and forced exercise. Dopamine metabolite content was decreased in the dorsal striatum and hypothalamus, and serotonin turnover increased in the dorsal striatum. The prefrontal cortex showed age-dependent changes in dopamine metabolites. The distribution of glutamate decarboxylase 67 (GAD67) protein and gamma-aminobutyric acid receptor type B receptor 1 (GABA R1) protein was altered in the dorsal striatum. In cultured neurons, wild-type Lrtm2 protein enhanced axon trafficking of GAD67-GFP and GABA R1-GFP whereas such activity was defective in sorting signal-abolished Lrtm2 mutant proteins. The topical expression of hemagglutinin-epitope-tag (HA)-Lrtm2 and a protein sorting signal abolished HA-Lrtm2 mutant differentially affected GABA R1 protein distribution in the dorsal striatum. These results suggest that Lrtm2 is an essential component of striatal projection neurons, contributing to a better understanding of striatal pathophysiology.

References

Heusner C, Beutler L, Houser C, Palmiter R . Deletion of GAD67 in dopamine receptor-1 expressing cells causes specific motor deficits. Genesis. 2008; 46(7):357-67. PMC: 3360952. DOI: 10.1002/dvg.20405. View

Zhai S, Tanimura A, Graves S, Shen W, Surmeier D . Striatal synapses, circuits, and Parkinson's disease. Curr Opin Neurobiol. 2017; 48:9-16. PMC: 6022405. DOI: 10.1016/j.conb.2017.08.004. View

Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene. 1991; 108(2):193-9. DOI: 10.1016/0378-1119(91)90434-d. View

Kanaani J, LISSIN D, Kash S, Baekkeskov S . The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to membranes and nerve terminals independent of dimerization with the hydrophobic membrane-anchored isoform, GAD65. J Biol Chem. 1999; 274(52):37200-9. DOI: 10.1074/jbc.274.52.37200. View

Wesolowska A, Nikiforuk A . Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression. Neuropharmacology. 2007; 52(5):1274-83. DOI: 10.1016/j.neuropharm.2007.01.007. View

Stoica L, Ahmed S, Gao G, Sena-Esteves M . Gene transfer to the CNS using recombinant adeno-associated virus. Curr Protoc Microbiol. 2013; Chapter 14:14D.5.1-14D.5.18. PMC: 4135440. DOI: 10.1002/9780471729259.mc14d05s29. View

Saura J, Richards J, Mahy N . Differential age-related changes of MAO-A and MAO-B in mouse brain and peripheral organs. Neurobiol Aging. 1994; 15(4):399-408. DOI: 10.1016/0197-4580(94)90071-x. View

Krismer F, Wenning G . Multiple system atrophy: insights into a rare and debilitating movement disorder. Nat Rev Neurol. 2017; 13(4):232-243. DOI: 10.1038/nrneurol.2017.26. View

Tekin M, Chioza B, Matsumoto Y, Diaz-Horta O, Cross H, Duman D . SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest. 2013; 123(5):2094-102. PMC: 3635725. DOI: 10.1172/JCI65853. View

10.

Carrel D, Simon A, Emerit M, Rivals I, Leterrier C, Biard M . Axonal targeting of the 5-HT1B serotonin receptor relies on structure-specific constitutive activation. Traffic. 2011; 12(11):1501-20. DOI: 10.1111/j.1600-0854.2011.01260.x. View

11.

Kratchmarov R, Taylor M, Enquist L . Role of Us9 phosphorylation in axonal sorting and anterograde transport of pseudorabies virus. PLoS One. 2013; 8(3):e58776. PMC: 3602541. DOI: 10.1371/journal.pone.0058776. View

12.

Morimura N, Yasuda H, Yamaguchi K, Katayama K, Hatayama M, Tomioka N . Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice. Nat Commun. 2017; 8:15800. PMC: 5472790. DOI: 10.1038/ncomms15800. View

13.

Lauren J, Airaksinen M, Saarma M, Timmusk T . A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics. 2003; 81(4):411-21. DOI: 10.1016/s0888-7543(03)00030-2. View

14.

Katayama K, Yamada K, Ornthanalai V, Inoue T, Ota M, Murphy N . Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities. Mol Psychiatry. 2008; 15(2):177-84. DOI: 10.1038/mp.2008.97. View

15.

Borgkvist A, Avegno E, Wong M, Kheirbek M, Sonders M, Hen R . Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice. Neuron. 2015; 87(5):976-88. PMC: 4559856. DOI: 10.1016/j.neuron.2015.08.022. View

16.

Takashima N, Odaka Y, Sakoori K, Akagi T, Hashikawa T, Morimura N . Impaired cognitive function and altered hippocampal synapse morphology in mice lacking Lrrtm1, a gene associated with schizophrenia. PLoS One. 2011; 6(7):e22716. PMC: 3144940. DOI: 10.1371/journal.pone.0022716. View

17.

Townsley F, Pelham H . The KKXX signal mediates retrieval of membrane proteins from the Golgi to the ER in yeast. Eur J Cell Biol. 1994; 64(1):211-6. View

18.

Wei J, Wu J . Post-translational regulation of L-glutamic acid decarboxylase in the brain. Neurochem Res. 2008; 33(8):1459-65. DOI: 10.1007/s11064-008-9600-5. View

19.

Festing M . On determining sample size in experiments involving laboratory animals. Lab Anim. 2018; 52(4):341-350. DOI: 10.1177/0023677217738268. View

20.

Schwenk J, Perez-Garci E, Schneider A, Kollewe A, Gauthier-Kemper A, Fritzius T . Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics. Nat Neurosci. 2015; 19(2):233-42. DOI: 10.1038/nn.4198. View