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

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

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 behavio...

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Published in:Frontiers in molecular neuroscience Vol. 15; p. 856315
Main Authors: Ichise, Misato, Sakoori, Kazuto, Katayama, Kei-Ichi, Morimura, Naoko, Yamada, Kazuyuki, Ozawa, Hiroki, Matsunaga, Hayato, Hatayama, Minoru, Aruga, Jun
Format: Journal Article
Language:English
Published: Switzerland Frontiers Research Foundation 09-05-2022
Frontiers Media S.A
Subjects:
Antibodies
behavioral abnormality
Biopsy
Brain
Caudate-putamen
Cloning
Dopamine
Epitopes
gene targeting
Glutamate decarboxylase
Hemagglutinins
Hypothalamus
Kinases
Lrtm2
Molecular weight
monoamine metabolism
Movement disorders
Mutants
Neostriatum
Neurological disorders
Neuroscience
Olfactory bulb
Peptides
Prefrontal cortex
Presynapse
protein sorting
Protein sorting signals
Protein transport
Proteins
Serotonin
striatal projection neuron
Transmembrane domains
γ-Aminobutyric acid
Japan
striatal projection neuron
behavioral abnormality
gene targeting
protein sorting
monoamine metabolism
Lrtm2
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Summary: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.
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These authors have contributed equally to this work and share first authorship
Reviewed by: Tsuyoshi Yamaguchi, Dokkyo Medical University, Japan; Tabrez Jamal Siddiqui, University of Manitoba, Canada
Edited by: Nobuyuki Takei, Niigata University, Japan
This article was submitted to Molecular Signalling and Pathways, a section of the journal Frontiers in Molecular Neuroscience
ISSN:1662-5099
1662-5099
DOI:10.3389/fnmol.2022.856315