TY - JOUR
T1 - Human induced pluripotent stem cell-derived dopaminergic neurons release alpha-synuclein through neuronal activity
AU - Nuermaimaiti, Maierdanjiang
AU - Ishikawa, Kei ichi
AU - Oyama, Genko
AU - Nonaka, Risa
AU - Shiga, Takahiro
AU - Jo, Takayuki
AU - Tsunemi, Taiji
AU - Nakamura, Ryota
AU - Krüger, Rejko
AU - Akamatsu, Wado
AU - Hattori, Nobutaka
N1 - Funding:
This work was funded by MEXT-Supported Programs for the Strategic Research Foundation at Private Universities (S1411007) and the Practical Research Project for Rare/Intractable Diseases (JP20ek0109429 to K-iI, GO, WA, and NH) from AMED, and a Grant-in-Aid for Scientific Research (20K07873 and 23K06934 to K-iI, 15K19498 and 18K07509 to GO, 20K07741 to RiN, and 18H04043 and 24H00068 to NH) from JSPS. Work of RK is supported by the National Centre of
Excellence in Research on Parkinson’s Disease (NCER-PD) (FNR;
NCER13/BM/11264123) and the PEARL program (PEARL /P13/6682797) funded by the Luxembourg National Research Fund (FNR).
This work was also partly supported by a Grant-in-Aid for Special
Research in Subsidies for ordinary expenses of private schools from The
Promotion and Mutual Aid Corporation for Private Schools of Japan.
Publisher Copyright:
© 2024 The Authors
PY - 2024/11/29
Y1 - 2024/11/29
N2 - 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.
AB - 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.
KW - Alpha-synuclein
KW - Human iPS cells
KW - Lewy body disease
KW - Neuronal activity
KW - Parkinson's disease
KW - Propagation
UR - http://www.scopus.com/inward/record.url?scp=85211167137&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/39617169/
U2 - 10.1016/j.neures.2024.11.007
DO - 10.1016/j.neures.2024.11.007
M3 - Article
C2 - 39617169
AN - SCOPUS:85211167137
SN - 0168-0102
JO - Neuroscience Research
JF - Neuroscience Research
ER -