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Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents

Author

Listed:
  • Yachao He

    (Karolinska Institutet)

  • Ibrahim Kaya

    (Uppsala University)

  • Reza Shariatgorji

    (Uppsala University
    Uppsala University)

  • Johan Lundkvist

    (Karolinska Institutet
    Sinfonia Biotherapeutics AB)

  • Lars U. Wahlberg

    (Karolinska Institutet)

  • Anna Nilsson

    (Uppsala University
    Uppsala University)

  • Dejan Mamula

    (Karolinska Institutet)

  • Jan Kehr

    (Karolinska Institute)

  • Justyna Zareba-Paslawska

    (Karolinska Institutet)

  • Henrik Biverstål

    (Sinfonia Biotherapeutics AB
    Karolinska Institutet)

  • Karima Chergui

    (Karolinska Institutet)

  • Xiaoqun Zhang

    (Karolinska Institutet)

  • Per E. Andren

    (Uppsala University
    Uppsala University)

  • Per Svenningsson

    (Karolinska Institutet
    King’s College London)

Abstract

Prosaposin (PSAP) modulates glycosphingolipid metabolism and variants have been linked to Parkinson’s disease (PD). Here, we find altered PSAP levels in the plasma, CSF and post-mortem brain of PD patients. Altered plasma and CSF PSAP levels correlate with PD-related motor impairments. Dopaminergic PSAP-deficient (cPSAPDAT) mice display hypolocomotion and depression/anxiety-like symptoms with mildly impaired dopaminergic neurotransmission, while serotonergic PSAP-deficient (cPSAPSERT) mice behave normally. Spatial lipidomics revealed an accumulation of highly unsaturated and shortened lipids and reduction of sphingolipids throughout the brains of cPSAPDAT mice. The overexpression of α-synuclein via AAV lead to more severe dopaminergic degeneration and higher p-Ser129 α-synuclein levels in cPSAPDAT mice compared to WT mice. Overexpression of PSAP via AAV and encapsulated cell biodelivery protected against 6-OHDA and α-synuclein toxicity in wild-type rodents. Thus, these findings suggest PSAP may maintain dopaminergic lipid homeostasis, which is dysregulated in PD, and counteract experimental parkinsonism.

Suggested Citation

  • Yachao He & Ibrahim Kaya & Reza Shariatgorji & Johan Lundkvist & Lars U. Wahlberg & Anna Nilsson & Dejan Mamula & Jan Kehr & Justyna Zareba-Paslawska & Henrik Biverstål & Karima Chergui & Xiaoqun Zhan, 2023. "Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41539-5
    DOI: 10.1038/s41467-023-41539-5
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    References listed on IDEAS

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    2. Xiaolai Zhou & Lirong Sun & Oliver Bracko & Ji Whae Choi & Yan Jia & Alissa L. Nana & Owen Adam Brady & Jean C. Cruz Hernandez & Nozomi Nishimura & William W. Seeley & Fenghua Hu, 2017. "Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    3. Marc Cruts & Ilse Gijselinck & Julie van der Zee & Sebastiaan Engelborghs & Hans Wils & Daniel Pirici & Rosa Rademakers & Rik Vandenberghe & Bart Dermaut & Jean-Jacques Martin & Cornelia van Duijn & K, 2006. "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21," Nature, Nature, vol. 442(7105), pages 920-924, August.
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