Daisuke Hatta

Nagasaki University

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PT608. Analysis of glutamate-induced processing of proline-rich transmembrane protein 2 (PRRT2)

The International Journal of Neuropsychopharmacology (2016)

Daisuke Hatta K KAJIYAMA Naohiro Kurotaki Hiroki Ozawa Masashi Asai

the number, mean duration and total duration of spike wave discharges (SWD) were evaluated using EEG recordings.Each group was then divided into two subgroups.In the first group mean arterial blood pressure (MAP) and heart rate (HR) measurements were performed.In the second group, in vitro isolated organ studies were conducted on the thoracic aortas of animals.Results: ETX treatment significantly reduced the number, mean duration and total duration of SWDs in WAG/Rij rats compared to control group.Wistar groups did not have any SWD.In WAG/ Rij control group, MAP was significantly higher than Wistar control.HR in Wistar ETX group was significantly lower than Wistar control group.KCl contraction responses increased in the Wistar ETX and decreased in the WAG/Rij control group compared to Wistar control group.Carbachol relaxation responses significantly increased in WAG/Rij control and decreased in Wistar ETX group compared to Wistar control group.There was no significant difference in sodium nitroprusside responses.Conclusions: Cardiovascular function changes have been observed in the WAG/Rij rats with AE and as a result of ethosuximide treatment, indicating that T-type calcium channels may play a major role in these changes.

10.1093/ijnp/pyw044.608

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Proline‐rich transmembrane protein 2 regulates the magnitude and frequency of dopamine release by repetitive neuronal stimuli in the striatum of L‐dopa‐treated mice

Neuropsychopharmacology Reports (2024)

Daisuke Hatta Shiho Makiya Kaito Kanamoto Kaori Watanabe Yuki Fuchigami

Abstract Mutations in proline‐rich transmembrane protein 2 ( PRRT2 ) cause paroxysmal kinesigenic dyskinesia (PKD). Recently, we reported that a Prrt2 mutation exacerbated L‐dopa‐induced motor deficits in mice, suggesting that the basal ganglia might contribute to PKD pathology. Here, we demonstrated that the Prrt2 mutation enhanced depolarization stimuli‐induced extracellular dopamine levels in the mouse striatum, which were attenuated by repeated stimulation. L‐dopa administration maintained high dopamine levels in Prrt2 ‐KI mice even during repetitive stimuli but did not affect dopamine levels in wild‐type mice. Thus, the enhanced and prolonged responsiveness of dopamine release in nigrostriatal dopaminergic neurons to sequential excitation may be partially implicated in Prrt2‐related dyskinesia.

Paroxysmal dyskinesia

10.1002/npr2.12478

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PT579. Disease-modifying therapy through enhancement of neuronal Aß-degrading enzyme neprilysin activity for Alzheimer’s disease

The International Journal of Neuropsychopharmacology (2016)

Nobuhisa Iwata Masashi Asai Daisuke Hatta Mikako Honda Yuma Hori

13 significant differences in the amyloid beta protein, Neprilysin (NEP), and SOX2 levels were not observed among the groups.Conclusion: Our study showed that a single dose of 1X10^6 hUCB-MSCs injected intravenously into AD transgenic mice resulted in neither delivery into the brain nor generation of therapeutic benefits via paracrine activity.In order to utilize the intravenous route as an effective delivery route for AD stem cell therapy, it will be crucial to perform additional studies on how to increase the permeability of the BBB and how to decrease the entrapment of cells in organs such as the lung and liver.

10.1093/ijnp/pyw044.579

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Issue Information

The FASEB Journal (2020)

Robert C. Goldman Stephen M. Hewitt Elizabeth A. Jonas Charles E. Kahn Patricia Morris

An adipose tissue galectin controls endothelial cell function via

10.1002/fsb2.20286

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Alterations of ATG4A and LC3B in neurons derived from Alzheimer's disease patients

Genes to Cells (2023)

Keiro Shirotani Kaori Watanabe Daisuke Hatta Yumiko Kutoku Yutaka Ohsawa

We investigated the alterations in autophagy-related molecules in neurons differentiated from induced pluripotent stem cells obtained from patients with Alzheimer's disease (AD). Consistent with our previous microarray data, ATG4A protein was upregulated in the neurons derived from a familial AD patient with an APP-E693Δ mutation who showed accumulation of intracellular amyloid β peptide (Aβ). This upregulation was reversed by inhibiting Aβ production, suggesting that the intracellular Aβ may be responsible for the upregulation of ATG4A. The LC3B-II/LC3B-I ratio, an index of autophagosome formation, was lower in the neurons derived from the AD patient with APP-E693Δ as well as the neurons derived from other familial and sporadic AD patients. These findings indicate that dysregulation of autophagy-related molecules may accelerate the pathogenesis of AD.

Pathogenesis

Amyloid (mycology)

10.1111/gtc.13010

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PROLINE-RICH TRANSMEMBRANE PROTEIN 2 KNOCK-IN MICE PRESENT NIGROSTRIATAL DOPAMINERGIC HYPERACTIVITY AND INCREASED SUSCEPTIBILITY TO L-DOPA-INDUCED MOTOR DEFICITS

The International Journal of Neuropsychopharmacology (2025)

Daisuke Hatta Kaito Kanamoto Shiho Makiya Kaori Watanabe Tatsuya Kishino

Abstract Mutations of proline-rich transmembrane protein 2 (PRRT2) lead to dyskinetic and convulsive disorders such as paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizure and hemiplegic migraine. PKD is characterized by attacks of involuntary movements precipitated by suddenly initiated motion. Previous studies have shown that PKD might be caused by cerebellar dysfunction; however, considering widespread expression of Prrt2 in the whole brain, it is likely that some other motor-related regions including the basal ganglia, where dopaminergic neurons are most abundant in the brain, might also be a part of pathogenesis of PKD. Here, we generated Prrt2 knock-in (KI) mice harboring mutation c.672dupG that mimics the human pathological mutation c.649dupC and investigated the role of Prrt2 in the basal ganglia. The mutant transcript and protein were abolished within the striatum, confirming loss-of-function nature of PKD and related disorders. Importantly, intrastriatal microdialysis revealed that the Prrt2 mutation dramatically elevated extracellular dopamine levels during the depolarized state, which might result from the increase in dopamine release because pharmacological inhibition of dopamine reuptake produced a greater elevation of extracellular dopamine levels in Prrt2-KI mice than in wild-type mice. Moreover, administration of L-dopa, a precursor of dopamine, exacerbated rotarod performance of Prrt2-KI mice more severely than that of wild-type mice. Overall, these findings suggest that dopaminergic dysfunction within the basal ganglia by the PRRT2 mutation might be implicated in a part of motor symptoms of PKD and related disorders.

10.1093/ijnp/pyae059.616

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Identification and Characterization of Synaptic Vesicle Membrane Protein VAT-1 Homolog as a New Catechin-Binding Protein

Biological and Pharmaceutical Bulletin (2024)

Ayaka Ikemizu Daisuke Hatta Kohei Fujimoto Mikako Honda Kaori Watanabe

(-)-Epigallocatechin-3-gallate (EGCg), a major constituent of green tea extract, is well-known to exhibit many beneficial actions for human health by interacting with numerous proteins. In this study we identified synaptic vesicle membrane protein VAT-1 homolog (VAT1) as a novel EGCg-binding protein in human neuroglioma cell extracts using a magnetic pull-down assay and LC-tandem mass spectrometry. We prepared recombinant human VAT1 and analyzed its direct binding to EGCg and its alkylated derivatives using surface plasmon resonance. For EGCg and the derivative NUP-15, we measured an association constant of 0.02-0.85 ×10

Dissociation constant

Ligand binding assay

Pyrogallol

Catechol

10.1248/bpb.b23-00830

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Proline-rich transmembrane protein 2 knock-in mice present dopamine-dependent motor deficits

The Journal of Biochemistry (2023)

Daisuke Hatta Kaito Kanamoto Shiho Makiya Kaori Watanabe Tatsuya Kishino

Mutations of proline-rich transmembrane protein 2 (PRRT2) lead to dyskinetic disorders such as paroxysmal kinesigenic dyskinesia (PKD), which is characterized by attacks of involuntary movements precipitated by suddenly initiated motion, and some convulsive disorders. Although previous studies have shown that PKD might be caused by cerebellar dysfunction, PRRT2 has not been sufficiently analyzed in some motor-related regions, including the basal ganglia, where dopaminergic neurons are most abundant in the brain. Here, we generated several types of Prrt2 knock-in (KI) mice harboring mutations, such as c.672dupG, that mimics the human pathological mutation c.649dupC and investigated the contribution of Prrt2 to dopaminergic regulation. Regardless of differences in the frameshift sites, all truncating mutations abolished Prrt2 expression within the striatum and cerebral cortex, consistent with previous reports of similar Prrt2 mutant rodents, confirming the loss-of-function nature of these mutations. Importantly, administration of l-dopa, a precursor of dopamine, exacerbated rotarod performance, especially in Prrt2-KI mice. These findings suggest that dopaminergic dysfunction in the brain by the PRRT2 mutation might be implicated in a part of motor symptoms of PKD and related disorders.

Paroxysmal dyskinesia

10.1093/jb/mvad074

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Activity‐dependent cleavage of dyskinesia‐related proline‐rich transmembrane protein 2 (PRRT2) by calpain in mouse primary cortical neurons

The FASEB Journal (2019)

Daisuke Hatta Keiro Shirotani Yuma Hori Naohiro Kurotaki Nobuhisa Iwata

Abstract Mutations of PRRT2 (proline‐rich transmembrane protein 2) cause several neurological disorders, represented by paroxysmal kinesigenic dyskinesia (PKD), which is characterized by attacks of involuntary movements triggered by sudden voluntary movements. PRRT2 is reported to suppress neuronal excitation, but it is unclear how the function of PRRT2 is modulated during neuronal excitation. We found that PRRT2 is processed to a 12 kDa carboxy‐terminal fragment (12K‐CTF) by calpain, a calcium‐activated cysteine protease, in a neuronal activity‐dependent manner, predominantly via NMDA receptors or voltage‐gated calcium channels. Furthermore, we clarified that 12K‐CTF is generated by sequential cleavages at Q220 and S244. The amino‐terminal fragment (NTF) of PRRT2, which corresponds to PKD‐related truncated mutants, is not detected, probably due to rapid cleavage at multiple positions. Given that 12K‐CTF lacks most of the proline‐rich domain, this cleavage might be involved in the activity‐dependent enhancement of neuronal excitation perhaps through transient retraction of PRRT2's function. Therefore, PRRT2 might serve as a buffer for neuronal excitation, and lack of this function in PKD patients might cause neuronal hyperexcitability in their motor circuits.

Paroxysmal dyskinesia

10.1096/fj.201902148r

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The role of TREM2 N-glycans in trafficking to the cell surface and signal transduction of TREM2

The Journal of Biochemistry (2022)

Keiro Shirotani Daisuke Hatta Naoki Wakita Kaori Watanabe Nobuhisa Iwata

Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer's disease, as well as other neurodegenerative disorders. TREM2 is glycosylated in vitro and in vivo, but the significance of the modification is unknown. We previously established a sensitive and specific reporter cell model involving cultured Jurkat cells stably expressing a luciferase reporter gene and a gene encoding a TREM2DAP12 fusion protein to monitor TREM2-dependent signalling. In the present study, we prepared modified reporter cells to investigate the role of the N-glycans at N20 and N79. We show that the N-glycans at N79 have a requisite role in translocation of TREM2 to the cell surface, while the N-glycans at both N20 and N79 have a critical role in intracellular signal transduction. Our results indicate that structural changes to the TREM2 N-glycans may cause microglial dysfunction that contributes to the pathogenesis of neurodegenerative disorders and that maintaining the integrity of TREM2 N-glycosylation and the responsible glycosyltransferases may be a novel therapeutic strategy to treat these disorders.

TREM2

Jurkat cells

Transduction (biophysics)

HEK 293 cells

10.1093/jb/mvac073

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Citations (7)