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Activation of ABCC1 transporter ameliorates synaptic dysregulation in Tay-Sachs disease neuron

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Title: Activation of ABCC1 transporter ameliorates synaptic dysregulation in Tay-Sachs disease neuron
Authors: Yumeng Zhang, Tadahiro Numakawa, Ryutaro Kajihara, Kiseok Lee, Jing Pu, Chisato Horita, Jun Kido, Muneaki Matsuo, Takumi Era
Source: Neurobiology of Disease, Vol 216, Iss , Pp 107099- (2025)
Publisher Information: Elsevier, 2025.
Publication Year: 2025
Collection: LCC:Neurosciences. Biological psychiatry. Neuropsychiatry
Subject Terms: Tay-sachs disease, GM2 ganglioside, Ca2+ influx, Synaptic function, ABCC1 transporter, Thiethylperazine, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Description: Tay-Sachs disease (TSD) is a congenital lysosomal storage disorder, caused by deficiency in the α-subunit of β-hexosaminidase A, leading to GM2 ganglioside accumulation in the central nervous system. Patients with TSD exhibit neural disturbances such as seizures, mental retardation; however, the molecular mechanisms behind neurological symptoms remain unclear. This study aimed to investigate altered synaptic function and explore treatment avenues for TSD. We observed the upregulation of postsynaptic receptors, abnormally elevated Ca2+ influx by neurotransmitter, and increased cell death under oxidative stress in TSD neurons. These abnormalities were associated with GM2 ganglioside accumulation. Additionally, we found that thiethylperazine, an approval drug for anti-emetics, mitigated GM2 ganglioside accumulation, potentially by activating the ATP-binding cassette subfamily C member 1 (ABCC1) transporter. This activation consequently improved the abnormal synaptic function. Our findings suggest that synaptic dysfunction is implicated in the neural disturbance in TSD, and highlight the ABCC1 transporter as a promising therapeutic target for this disease.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1095-953X
Relation: http://www.sciencedirect.com/science/article/pii/S096999612500316X; https://doaj.org/toc/1095-953X
DOI: 10.1016/j.nbd.2025.107099
Access URL: https://doaj.org/article/d149617c31fa45df8bedacbdde1732b9
Accession Number: edsdoj.149617c31fa45df8bedacbdde1732b9
Database: Directory of Open Access Journals
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  Data: Activation of ABCC1 transporter ameliorates synaptic dysregulation in Tay-Sachs disease neuron
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  Data: <searchLink fieldCode="AR" term="%22Yumeng+Zhang%22">Yumeng Zhang</searchLink><br /><searchLink fieldCode="AR" term="%22Tadahiro+Numakawa%22">Tadahiro Numakawa</searchLink><br /><searchLink fieldCode="AR" term="%22Ryutaro+Kajihara%22">Ryutaro Kajihara</searchLink><br /><searchLink fieldCode="AR" term="%22Kiseok+Lee%22">Kiseok Lee</searchLink><br /><searchLink fieldCode="AR" term="%22Jing+Pu%22">Jing Pu</searchLink><br /><searchLink fieldCode="AR" term="%22Chisato+Horita%22">Chisato Horita</searchLink><br /><searchLink fieldCode="AR" term="%22Jun+Kido%22">Jun Kido</searchLink><br /><searchLink fieldCode="AR" term="%22Muneaki+Matsuo%22">Muneaki Matsuo</searchLink><br /><searchLink fieldCode="AR" term="%22Takumi+Era%22">Takumi Era</searchLink>
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  Data: Neurobiology of Disease, Vol 216, Iss , Pp 107099- (2025)
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  Data: Elsevier, 2025.
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  Data: 2025
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  Data: LCC:Neurosciences. Biological psychiatry. Neuropsychiatry
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  Data: <searchLink fieldCode="DE" term="%22Tay-sachs+disease%22">Tay-sachs disease</searchLink><br /><searchLink fieldCode="DE" term="%22GM2+ganglioside%22">GM2 ganglioside</searchLink><br /><searchLink fieldCode="DE" term="%22Ca2%2B+influx%22">Ca2+ influx</searchLink><br /><searchLink fieldCode="DE" term="%22Synaptic+function%22">Synaptic function</searchLink><br /><searchLink fieldCode="DE" term="%22ABCC1+transporter%22">ABCC1 transporter</searchLink><br /><searchLink fieldCode="DE" term="%22Thiethylperazine%22">Thiethylperazine</searchLink><br /><searchLink fieldCode="DE" term="%22Neurosciences%2E+Biological+psychiatry%2E+Neuropsychiatry%22">Neurosciences. Biological psychiatry. Neuropsychiatry</searchLink><br /><searchLink fieldCode="DE" term="%22RC321-571%22">RC321-571</searchLink>
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  Data: Tay-Sachs disease (TSD) is a congenital lysosomal storage disorder, caused by deficiency in the α-subunit of β-hexosaminidase A, leading to GM2 ganglioside accumulation in the central nervous system. Patients with TSD exhibit neural disturbances such as seizures, mental retardation; however, the molecular mechanisms behind neurological symptoms remain unclear. This study aimed to investigate altered synaptic function and explore treatment avenues for TSD. We observed the upregulation of postsynaptic receptors, abnormally elevated Ca2+ influx by neurotransmitter, and increased cell death under oxidative stress in TSD neurons. These abnormalities were associated with GM2 ganglioside accumulation. Additionally, we found that thiethylperazine, an approval drug for anti-emetics, mitigated GM2 ganglioside accumulation, potentially by activating the ATP-binding cassette subfamily C member 1 (ABCC1) transporter. This activation consequently improved the abnormal synaptic function. Our findings suggest that synaptic dysfunction is implicated in the neural disturbance in TSD, and highlight the ABCC1 transporter as a promising therapeutic target for this disease.
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      – Text: English
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      – SubjectFull: Tay-sachs disease
        Type: general
      – SubjectFull: GM2 ganglioside
        Type: general
      – SubjectFull: Ca2+ influx
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