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

Autor: 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, Per Svenningsson
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Nature Communications, Vol 14, Iss 1, Pp 1-22 (2023)
Druh dokumentu: article
ISSN: 2041-1723
DOI: 10.1038/s41467-023-41539-5
Popis: 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.
Databáze: Directory of Open Access Journals
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