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Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease

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  • Soojin Kim

    (Northwestern University Feinberg School of Medicine)

  • Yvette C. Wong

    (Northwestern University Feinberg School of Medicine)

  • Fanding Gao

    (Northwestern University Feinberg School of Medicine)

  • Dimitri Krainc

    (Northwestern University Feinberg School of Medicine)

Abstract

Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. In this study, we demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons, allowing for their bidirectional crosstalk. Parkinson’s disease patient derived neurons harboring mutant GBA1 exhibited prolonged mitochondria-lysosome contacts due to defective modulation of the untethering protein TBC1D15, which mediates Rab7 GTP hydrolysis for contact untethering. This dysregulation was due to decreased GBA1 (β-glucocerebrosidase (GCase)) lysosomal enzyme activity in patient derived neurons, and could be rescued by increasing enzyme activity with a GCase modulator. These defects resulted in disrupted mitochondrial distribution and function, and could be further rescued by TBC1D15 in Parkinson’s patient derived GBA1-linked neurons. Together, our work demonstrates a potential role of mitochondria-lysosome contacts as an upstream regulator of mitochondrial function and dynamics in midbrain dopaminergic neurons in GBA1-linked Parkinson’s disease.

Suggested Citation

  • Soojin Kim & Yvette C. Wong & Fanding Gao & Dimitri Krainc, 2021. "Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22113-3
    DOI: 10.1038/s41467-021-22113-3
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    Cited by:

    1. Katelyn C. Cook & Elene Tsopurashvili & Jason M. Needham & Sunnie R. Thompson & Ileana M. Cristea, 2022. "Restructured membrane contacts rewire organelles for human cytomegalovirus infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Zoë P. Van Acker & Anika Perdok & Ruben Hellemans & Katherine North & Inge Vorsters & Cedric Cappel & Jonas Dehairs & Johannes V. Swinnen & Ragna Sannerud & Marine Bretou & Markus Damme & Wim Annaert, 2023. "Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Wei Jiang & Qing Li & Ruofei Zhang & Jianru Li & Qianyu Lin & Jingyun Li & Xinyao Zhou & Xiyun Yan & Kelong Fan, 2023. "Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Hideyuki Takahashi & Sanaea Bhagwagar & Sarah H. Nies & Hongping Ye & Xianlin Han & Marius T. Chiasseu & Guilin Wang & Ian R. Mackenzie & Stephen M. Strittmatter, 2024. "Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    5. Flavia Giamogante & Lucia Barazzuol & Francesca Maiorca & Elena Poggio & Alessandra Esposito & Anna Masato & Gennaro Napolitano & Alessio Vagnoni & Tito Calì & Marisa Brini, 2024. "A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$ α -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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