Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality

Jonas Walter; Silvia Bolognin; Paul M.A. Antony; Sarah L. Nickels; Suresh K. Poovathingal; Luis Salamanca; Stefano Magni; Rita Perfeito; Fredrik Hoel; Xiaobing Qing; Javier Jarazo; Jonathan Arias-Fuenzalida; Tomasz Ignac; Anna S. Monzel; Laura Gonzalez-Cano; Luis Pereira de Almeida; Alexander Skupin; Karl J. Tronstad; Jens C. Schwamborn

doi:10.1016/j.stemcr.2019.03.004

Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality

Jonas Walter, Silvia Bolognin, Paul M.A. Antony, Sarah L. Nickels, Suresh K. Poovathingal, Luis Salamanca, Stefano Magni, Rita Perfeito, Fredrik Hoel, Xiaobing Qing, Javier Jarazo, Jonathan Arias-Fuenzalida, Tomasz Ignac, Anna S. Monzel, Laura Gonzalez-Cano, Luis Pereira de Almeida, Alexander Skupin, Karl J. Tronstad, Jens C. Schwamborn^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

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Abstract

Emerging evidence suggests that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs), carrying the LRRK2-G2019S mutation, recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation causes aberrations in mitochondrial morphology and functionality compared with isogenic controls. LRRK2-G2019S NESCs display an increased number of mitochondria compared with isogenic control lines. However, these mitochondria are more fragmented and exhibit decreased membrane potential. Functional alterations in LRRK2-G2019S cultures are also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life.

Original language	English
Pages (from-to)	878-889
Number of pages	12
Journal	Stem Cell Reports
Volume	12
Issue number	5
DOIs	https://doi.org/10.1016/j.stemcr.2019.03.004
Publication status	Published - 14 May 2019
Externally published	Yes

Keywords

LRRK2
Parkinson's disease
autophagy
mitochondria
mitophagy
neurodevelopment
stem cells

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10.1016/j.stemcr.2019.03.004

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Walter, J., Bolognin, S., Antony, P. M. A., Nickels, S. L., Poovathingal, S. K., Salamanca, L., Magni, S., Perfeito, R., Hoel, F., Qing, X., Jarazo, J., Arias-Fuenzalida, J., Ignac, T., Monzel, A. S., Gonzalez-Cano, L., Pereira de Almeida, L., Skupin, A., Tronstad, K. J., & Schwamborn, J. C. (2019). Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality. Stem Cell Reports, 12(5), 878-889. https://doi.org/10.1016/j.stemcr.2019.03.004

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title = "Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality",

abstract = "Emerging evidence suggests that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs), carrying the LRRK2-G2019S mutation, recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation causes aberrations in mitochondrial morphology and functionality compared with isogenic controls. LRRK2-G2019S NESCs display an increased number of mitochondria compared with isogenic control lines. However, these mitochondria are more fragmented and exhibit decreased membrane potential. Functional alterations in LRRK2-G2019S cultures are also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life.",

keywords = "LRRK2, Parkinson's disease, autophagy, mitochondria, mitophagy, neurodevelopment, stem cells",

author = "Jonas Walter and Silvia Bolognin and Antony, \{Paul M.A.\} and Nickels, \{Sarah L.\} and Poovathingal, \{Suresh K.\} and Luis Salamanca and Stefano Magni and Rita Perfeito and Fredrik Hoel and Xiaobing Qing and Javier Jarazo and Jonathan Arias-Fuenzalida and Tomasz Ignac and Monzel, \{Anna S.\} and Laura Gonzalez-Cano and \{Pereira de Almeida\}, Luis and Alexander Skupin and Tronstad, \{Karl J.\} and Schwamborn, \{Jens C.\}",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = may,

day = "14",

doi = "10.1016/j.stemcr.2019.03.004",

language = "English",

volume = "12",

pages = "878--889",

journal = "Stem Cell Reports",

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Walter, J, Bolognin, S, Antony, PMA, Nickels, SL, Poovathingal, SK, Salamanca, L, Magni, S, Perfeito, R, Hoel, F, Qing, X, Jarazo, J, Arias-Fuenzalida, J, Ignac, T, Monzel, AS, Gonzalez-Cano, L, Pereira de Almeida, L, Skupin, A, Tronstad, KJ & Schwamborn, JC 2019, 'Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality', Stem Cell Reports, vol. 12, no. 5, pp. 878-889. https://doi.org/10.1016/j.stemcr.2019.03.004

TY - JOUR

T1 - Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality

AU - Walter, Jonas

AU - Bolognin, Silvia

AU - Antony, Paul M.A.

AU - Nickels, Sarah L.

AU - Poovathingal, Suresh K.

AU - Salamanca, Luis

AU - Magni, Stefano

AU - Perfeito, Rita

AU - Hoel, Fredrik

AU - Qing, Xiaobing

AU - Jarazo, Javier

AU - Arias-Fuenzalida, Jonathan

AU - Ignac, Tomasz

AU - Monzel, Anna S.

AU - Gonzalez-Cano, Laura

AU - Pereira de Almeida, Luis

AU - Skupin, Alexander

AU - Tronstad, Karl J.

AU - Schwamborn, Jens C.

PY - 2019/5/14

Y1 - 2019/5/14

N2 - Emerging evidence suggests that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs), carrying the LRRK2-G2019S mutation, recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation causes aberrations in mitochondrial morphology and functionality compared with isogenic controls. LRRK2-G2019S NESCs display an increased number of mitochondria compared with isogenic control lines. However, these mitochondria are more fragmented and exhibit decreased membrane potential. Functional alterations in LRRK2-G2019S cultures are also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life.

AB - Emerging evidence suggests that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs), carrying the LRRK2-G2019S mutation, recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation causes aberrations in mitochondrial morphology and functionality compared with isogenic controls. LRRK2-G2019S NESCs display an increased number of mitochondria compared with isogenic control lines. However, these mitochondria are more fragmented and exhibit decreased membrane potential. Functional alterations in LRRK2-G2019S cultures are also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life.

KW - LRRK2

KW - Parkinson's disease

KW - autophagy

KW - mitochondria

KW - mitophagy

KW - neurodevelopment

KW - stem cells

UR - https://www.scopus.com/pages/publications/85065141489

U2 - 10.1016/j.stemcr.2019.03.004

DO - 10.1016/j.stemcr.2019.03.004

M3 - Article

C2 - 30982740

AN - SCOPUS:85065141489

SN - 2213-6711

VL - 12

SP - 878

EP - 889

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 5

ER -

Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality

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Keywords

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