Human induced pluripotent stem cell-derived dopaminergic neurons release alpha-synuclein through neuronal activity

Maierdanjiang Nuermaimaiti; Kei-Ichi Ishikawa; Genko Oyama; Risa Nonaka; Takahiro Shiga; Takayuki Jo; Taiji Tsunemi; Ryota Nakamura; Rejko Krüger; Wado Akamatsu; Nobutaka Hattori

doi:10.1016/j.neures.2024.11.007

Human induced pluripotent stem cell-derived dopaminergic neurons release alpha-synuclein through neuronal activity

Neurosci Res. 2024 Nov 29:S0168-0102(24)00140-8. doi: 10.1016/j.neures.2024.11.007. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Department of Clinical Data of Parkinson's Disease, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
² Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Research and Development for Organoids, School of Medicine, Juntendo University, Tokyo, Japan. Electronic address: kishikaw@juntendo.ac.jp.
³ Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan.
⁴ Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Laboratory of Molecular Biology, Faculty of Pharmacy, Juntendo University, Chiba, Japan.
⁵ Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
⁶ Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Luxembourg Institute of Health, Strassen, Luxembourg; Centre Hospitalier de Luxembourg, Luxembourg.
⁷ Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Department of Clinical Data of Parkinson's Disease, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Research and Development for Organoids, School of Medicine, Juntendo University, Tokyo, Japan; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Luxembourg Institute of Health, Strassen, Luxembourg; Centre Hospitalier de Luxembourg, Luxembourg; Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama, Japan.

PMID: 39617169
DOI: 10.1016/j.neures.2024.11.007

Abstract

Lewy body diseases, including Parkinson's disease (PD), are characterized by the spread of alpha-synuclein (αSyn) between neurons across synapses, a process crucial for understanding their pathophysiology and developing effective treatments. In this study, we aimed to investigate the role of neuronal activity in releasing αSyn from human induced pluripotent stem cell-derived dopaminergic neurons. We examined human induced pluripotent stem cell-derived dopaminergic neurons, both healthy and those with the αSyn gene mutation associated with PD. We employed pharmacological agents and optogenetic techniques and demonstrated that increased neuronal activity, induced by bicuculline or optogenetic stimulation, significantly enhances αSyn release. However, suppression of neuronal activity with cyanquixaline reduces αSyn secretion. These findings underscore the pivotal role of neuronal activity in αSyn transmission between neurons, showing its potential impact on the spread of Lewy pathology in patients with neurodegenerative diseases like PD. Therefore, this study advances our understanding of PD and opens new avenues for therapeutic strategies to mitigate Lewy body disease progression.

Keywords: Alpha-synuclein; Human iPS cells; Lewy body disease; Neuronal activity; Parkinson’s disease; Propagation.