Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease

Fikret Emre Kapucu; Iisa Tujula; Oskari Kulta; Lassi Sukki; Tomi Ryynänen; Hjalte Gram; Valtteri Vuolanto; Andrey Vinogradov; Joose Kreutzer; Poul Henning Jensen; Pasi Kallio; Susanna Narkilahti

doi:10.1038/s41531-024-00750-x

Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease

Fikret Emre Kapucu^*, Iisa Tujula, Oskari Kulta, Lassi Sukki, Tomi Ryynänen, Hjalte Gram, Valtteri Vuolanto, Andrey Vinogradov, Joose Kreutzer, Poul Henning Jensen, Pasi Kallio, Susanna Narkilahti

^*Corresponding author for this work

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Abstract

Previous studies have shown that aggregated alpha-synuclein (α-s) protein, a key pathological marker of Parkinson’s disease (PD), can propagate between cells, thus participating in disease progression. This prion-like propagation has been widely studied using in vivo and in vitro models, including rodent and human cell cultures. In this study, our focus was on temporal assessment of functional changes during α-s aggregation and propagation in human induced pluripotent stem cell (hiPSC)-derived neuronal cultures and in engineered networks. Here, we report an engineered circular tripartite human neuronal network model in a microfluidic chip integrated with microelectrode arrays (MEAs) as a platform to study functional markers during α-s aggregation and propagation. We observed progressive aggregation of α-s in conventional neuronal cultures and in the exposed (proximal) compartments of circular tripartite networks following exposure to preformed α-s fibrils (PFF). Furthermore, aggregated forms propagated to distal compartments of the circular tripartite networks through axonal transport. We observed impacts of α-s aggregation on both the structure and function of neuronal cells, such as in presynaptic proteins, mitochondrial motility, calcium oscillations and neuronal activity. The model enabled an assessment of the early, middle, and late phases of α-s aggregation and its propagation during a 13-day follow-up period. While our temporal analysis suggested a complex interplay of structural and functional changes during the in vitro propagation of α-s aggregates, further investigation is required to elucidate the underlying mechanisms. Taken together, this study demonstrates the technical potential of our introduced model for conducting in-depth analyses for revealing such mechanisms.

Original language	English
Article number	138
Journal	npj Parkinson's Disease
Volume	10
Issue	1
ISSN	2373-8057
DOIs	https://doi.org/10.1038/s41531-024-00750-x
Publication status	Published - Dec 2024

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Kapucu, F. E., Tujula, I., Kulta, O., Sukki, L., Ryynänen, T., Gram, H., Vuolanto, V., Vinogradov, A., Kreutzer, J., Jensen, P. H., Kallio, P., & Narkilahti, S. (2024). Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease. npj Parkinson's Disease , 10(1), Article 138. https://doi.org/10.1038/s41531-024-00750-x

@article{50a36b05965948bd9038e3d706906dfb,

title = "Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson{\textquoteright}s Disease",

abstract = "Previous studies have shown that aggregated alpha-synuclein (α-s) protein, a key pathological marker of Parkinson{\textquoteright}s disease (PD), can propagate between cells, thus participating in disease progression. This prion-like propagation has been widely studied using in vivo and in vitro models, including rodent and human cell cultures. In this study, our focus was on temporal assessment of functional changes during α-s aggregation and propagation in human induced pluripotent stem cell (hiPSC)-derived neuronal cultures and in engineered networks. Here, we report an engineered circular tripartite human neuronal network model in a microfluidic chip integrated with microelectrode arrays (MEAs) as a platform to study functional markers during α-s aggregation and propagation. We observed progressive aggregation of α-s in conventional neuronal cultures and in the exposed (proximal) compartments of circular tripartite networks following exposure to preformed α-s fibrils (PFF). Furthermore, aggregated forms propagated to distal compartments of the circular tripartite networks through axonal transport. We observed impacts of α-s aggregation on both the structure and function of neuronal cells, such as in presynaptic proteins, mitochondrial motility, calcium oscillations and neuronal activity. The model enabled an assessment of the early, middle, and late phases of α-s aggregation and its propagation during a 13-day follow-up period. While our temporal analysis suggested a complex interplay of structural and functional changes during the in vitro propagation of α-s aggregates, further investigation is required to elucidate the underlying mechanisms. Taken together, this study demonstrates the technical potential of our introduced model for conducting in-depth analyses for revealing such mechanisms.",

author = "Kapucu, {Fikret Emre} and Iisa Tujula and Oskari Kulta and Lassi Sukki and Tomi Ryyn{\"a}nen and Hjalte Gram and Valtteri Vuolanto and Andrey Vinogradov and Joose Kreutzer and Jensen, {Poul Henning} and Pasi Kallio and Susanna Narkilahti",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41531-024-00750-x",

language = "English",

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Kapucu, FE, Tujula, I, Kulta, O, Sukki, L, Ryynänen, T, Gram, H, Vuolanto, V, Vinogradov, A, Kreutzer, J, Jensen, PH, Kallio, P & Narkilahti, S 2024, 'Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease', npj Parkinson's Disease , vol. 10, no. 1, 138. https://doi.org/10.1038/s41531-024-00750-x

Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease. / Kapucu, Fikret Emre; Tujula, Iisa; Kulta, Oskari et al.
In: npj Parkinson's Disease , Vol. 10, No. 1, 138, 12.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease

AU - Kapucu, Fikret Emre

AU - Tujula, Iisa

AU - Kulta, Oskari

AU - Sukki, Lassi

AU - Ryynänen, Tomi

AU - Gram, Hjalte

AU - Vuolanto, Valtteri

AU - Vinogradov, Andrey

AU - Kreutzer, Joose

AU - Jensen, Poul Henning

AU - Kallio, Pasi

AU - Narkilahti, Susanna

PY - 2024/12

Y1 - 2024/12

N2 - Previous studies have shown that aggregated alpha-synuclein (α-s) protein, a key pathological marker of Parkinson’s disease (PD), can propagate between cells, thus participating in disease progression. This prion-like propagation has been widely studied using in vivo and in vitro models, including rodent and human cell cultures. In this study, our focus was on temporal assessment of functional changes during α-s aggregation and propagation in human induced pluripotent stem cell (hiPSC)-derived neuronal cultures and in engineered networks. Here, we report an engineered circular tripartite human neuronal network model in a microfluidic chip integrated with microelectrode arrays (MEAs) as a platform to study functional markers during α-s aggregation and propagation. We observed progressive aggregation of α-s in conventional neuronal cultures and in the exposed (proximal) compartments of circular tripartite networks following exposure to preformed α-s fibrils (PFF). Furthermore, aggregated forms propagated to distal compartments of the circular tripartite networks through axonal transport. We observed impacts of α-s aggregation on both the structure and function of neuronal cells, such as in presynaptic proteins, mitochondrial motility, calcium oscillations and neuronal activity. The model enabled an assessment of the early, middle, and late phases of α-s aggregation and its propagation during a 13-day follow-up period. While our temporal analysis suggested a complex interplay of structural and functional changes during the in vitro propagation of α-s aggregates, further investigation is required to elucidate the underlying mechanisms. Taken together, this study demonstrates the technical potential of our introduced model for conducting in-depth analyses for revealing such mechanisms.

AB - Previous studies have shown that aggregated alpha-synuclein (α-s) protein, a key pathological marker of Parkinson’s disease (PD), can propagate between cells, thus participating in disease progression. This prion-like propagation has been widely studied using in vivo and in vitro models, including rodent and human cell cultures. In this study, our focus was on temporal assessment of functional changes during α-s aggregation and propagation in human induced pluripotent stem cell (hiPSC)-derived neuronal cultures and in engineered networks. Here, we report an engineered circular tripartite human neuronal network model in a microfluidic chip integrated with microelectrode arrays (MEAs) as a platform to study functional markers during α-s aggregation and propagation. We observed progressive aggregation of α-s in conventional neuronal cultures and in the exposed (proximal) compartments of circular tripartite networks following exposure to preformed α-s fibrils (PFF). Furthermore, aggregated forms propagated to distal compartments of the circular tripartite networks through axonal transport. We observed impacts of α-s aggregation on both the structure and function of neuronal cells, such as in presynaptic proteins, mitochondrial motility, calcium oscillations and neuronal activity. The model enabled an assessment of the early, middle, and late phases of α-s aggregation and its propagation during a 13-day follow-up period. While our temporal analysis suggested a complex interplay of structural and functional changes during the in vitro propagation of α-s aggregates, further investigation is required to elucidate the underlying mechanisms. Taken together, this study demonstrates the technical potential of our introduced model for conducting in-depth analyses for revealing such mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=85199982412&partnerID=8YFLogxK

U2 - 10.1038/s41531-024-00750-x

DO - 10.1038/s41531-024-00750-x

M3 - Journal article

C2 - 39069518

AN - SCOPUS:85199982412

SN - 2373-8057

VL - 10

JO - npj Parkinson's Disease

JF - npj Parkinson's Disease

IS - 1

M1 - 138

ER -

Human tripartite cortical network model for temporal assessment of alpha-synuclein aggregation and propagation in Parkinson’s Disease

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