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Peer-reviewedCC BY 4.0Frontiers in Neurology

Dibucaine induces autophagic flux and reduces Ser129-phosphorylated α-synuclein in induced pluripotent stem cell–derived neurons with SNCA duplication

  • Mitsuhiro Kitagawa1
  • Kengo Miyamoto2
  • Kozo Yoshida2
  • Kei-Ichi Ishikawa1,3
  • Yukiko Sasazawa1,4,5
  • Wado Akamatsu3
  • Shinji Saiki1,5,6
  • Taku Hatano1,6
  • Masaya Imoto1,6
  • Hidetaka Nagata2
  • Nobutaka Hattori1,4,6,7
7 affiliations
  1. 1Department of Neurology, Juntendo University Faculty of Medicine
  2. 2Sumitomo Pharma Co., Ltd.
  3. 3Center for Genomic and Regenerative Medicine, Juntendo University Graduate School of Medicine
  4. 4Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine
  5. 5Division for Development of Autophagy Modulating Drugs, Juntendo University Faculty of Medicine
  6. 6Department of Neurology, Institute of Medicine, University of Tsukuba
  7. 7Neurodegenerative Disorders Collaboration Laboratory, RIKEN Center for Brain Science
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Abstract

The accumulation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites is a neuropathological hallmark of Parkinson’s disease (PD) and is closely associated with disease progression. Targeting the autophagy pathway to enhance the clearance of α-syn aggregates therefore represents a promising therapeutic strategy. In the present study, we conducted high-throughput screening using rat embryonic primary neurons, followed by validation of the identified compounds in human induced pluripotent stem cell (iPSC)-derived neurons. We identified dibucaine, a local anesthetic, as a compound that induced autophagic flux in neuronal models. In human iPSC-derived dopaminergic neurons from a patient with PD carrying an SNCA duplication, dibucaine reduced cellular levels of Ser129-phosphorylated α-synuclein (pS129 α-syn). In SH-SY5Y cells, dibucaine increased 5’-AMP-activated protein kinase (AMPK) Thr172 phosphorylation. LY364947 partially attenuated dibucaine-induced LC3-II accumulation in the iPSC-derived neurons through an unidentified mechanism. Although the requirement for AMPK and the mechanism underlying the reduction in pS129 α-syn remain unresolved, our findings show that dibucaine induces autophagic flux and reduces pS129 α-syn levels in disease-relevant human neurons.

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Cite

BibTeXRIS
BibTeX
@article{kitagawa2026dibucaine,
  title = {{Dibucaine induces autophagic flux and reduces Ser129-phosphorylated α-synuclein in induced pluripotent stem cell–derived neurons with SNCA duplication}},
  author = {Mitsuhiro Kitagawa and Kengo Miyamoto and Kozo Yoshida and Kei-Ichi Ishikawa and Yukiko Sasazawa and Wado Akamatsu and Shinji Saiki and Taku Hatano and Masaya Imoto and Hidetaka Nagata and Nobutaka Hattori},
  journal = {Frontiers in Neurology},
  year = {2026},
  month = oct,
  doi = {10.3389/fneur.2026.1891393},
  url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1891393/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Dibucaine induces autophagic flux and reduces Ser129-phosphorylated α-synuclein in induced pluripotent stem cell–derived neurons with SNCA duplication
AU  - Mitsuhiro Kitagawa
AU  - Kengo Miyamoto
AU  - Kozo Yoshida
AU  - Kei-Ichi Ishikawa
AU  - Yukiko Sasazawa
AU  - Wado Akamatsu
AU  - Shinji Saiki
AU  - Taku Hatano
AU  - Masaya Imoto
AU  - Hidetaka Nagata
AU  - Nobutaka Hattori
PY  - 2026
DA  - 2026/10/08
JO  - Frontiers in Neurology
DO  - 10.3389/fneur.2026.1891393
UR  - https://www.frontiersin.org/articles/10.3389/fneur.2026.1891393/full
AB  - The accumulation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites is a neuropathological hallmark of Parkinson’s disease (PD) and is closely associated with disease progression. Targeting the autophagy pathway to enhance the clearance of α-syn aggregates therefore represents a promising therapeutic strategy. In the present study, we conducted high-throughput screening using rat embryonic primary neurons, followed by validation of the identified compounds in human induced pluripotent stem cell (iPSC)-derived neurons. We identified dibucaine, a local anesthetic, as a compound that induced autophagic flux in neuronal models. In human iPSC-derived dopaminergic neurons from a patient with PD carrying an SNCA duplication, dibucaine reduced cellular levels of Ser129-phosphorylated α-synuclein (pS129 α-syn). In SH-SY5Y cells, dibucaine increased 5’-AMP-activated protein kinase (AMPK) Thr172 phosphorylation. LY364947 partially attenuated dibucaine-induced LC3-II accumulation in the iPSC-derived neurons through an unidentified mechanism. Although the requirement for AMPK and the mechanism underlying the reduction in pS129 α-syn remain unresolved, our findings show that dibucaine induces autophagic flux and reduces pS129 α-syn levels in disease-relevant human neurons.
SN  - 1664-2295
ER  -