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

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 Zhang, Per E. Andren and Per Svenningsson ()
Additional contact information
Yachao He: Karolinska Institutet
Ibrahim Kaya: Uppsala University
Reza Shariatgorji: Uppsala University
Johan Lundkvist: Karolinska Institutet
Lars U. Wahlberg: Karolinska Institutet
Anna Nilsson: Uppsala University
Dejan Mamula: Karolinska Institutet
Jan Kehr: Karolinska Institute
Justyna Zareba-Paslawska: Karolinska Institutet
Henrik Biverstål: Sinfonia Biotherapeutics AB
Karima Chergui: Karolinska Institutet
Xiaoqun Zhang: Karolinska Institutet
Per E. Andren: Uppsala University
Per Svenningsson: Karolinska Institutet

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41539-5

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