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

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He Y, Kaya I, Shariatgorji R, Lundkvist J, Wahlberg LU, Nilsson A, Mamula D, Kehr J, Zareba-Paslawska J, Biverstål H, Chergui K, Zhang X, Andren PE, Svenningsson P

Nat Commun 14 (1) 5804 [2023-09-19; online 2023-09-19]

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.

Spatial Mass Spectrometry [Collaborative]

PubMed 37726325

DOI 10.1038/s41467-023-41539-5

Crossref 10.1038/s41467-023-41539-5

pmc: PMC10509278
pii: 10.1038/s41467-023-41539-5