| First Author | He Y | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 5804 |
| PubMed ID | 37726325 | Mgi Jnum | J:340806 |
| Mgi Id | MGI:7530302 | Doi | 10.1038/s41467-023-41539-5 |
| Citation | He Y, et al. (2023) Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents. Nat Commun 14(1):5804 |
| abstractText | 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 (cPSAP(DAT)) mice display hypolocomotion and depression/anxiety-like symptoms with mildly impaired dopaminergic neurotransmission, while serotonergic PSAP-deficient (cPSAP(SERT)) mice behave normally. Spatial lipidomics revealed an accumulation of highly unsaturated and shortened lipids and reduction of sphingolipids throughout the brains of cPSAP(DAT) mice. The overexpression of alpha-synuclein via AAV lead to more severe dopaminergic degeneration and higher p-Ser129 alpha-synuclein levels in cPSAP(DAT) mice compared to WT mice. Overexpression of PSAP via AAV and encapsulated cell biodelivery protected against 6-OHDA and alpha-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. |
