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- He, Yachao
(author)
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Bridging the gap between lipid dyshomeostasis and brain disorders : role of prosaposin and progranulin
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Brain tissue is the second-highest lipid-containing tissue after adipose in the human body. Lipid homeostasis maintenance requires the coordination of multiple cellular organelles. Pathogenesis of brain disorders, especially Parkinson’s disease (PD), usually involves different dysfunctional pathways that intimately link to lipid homeostasis. Indeed, lipid dyshomeostasis, especially disruption in sphingolipid metabolism, is a critical factor of several common brain disorders, including PD and schizophrenia, and rarer, Gaucher’s disease and Niemann-Picks disease, and probably underlies the dysfunctional pathways contributing to these diseases. Up till now, explanations of various lipid alterations in different disease conditions are lacking, let alone a factor that unifies the principles underlying lipid dyshomeostasis across different diseases. However, recently two lysosomal proteins, prosaposin (PSAP) and progranulin (PGRN), displayed the potential to lend mechanisms to widespread lipid changes across different diseases, which may be a good example to bridge the gap between lipid dyshomeostasis and brain disorders. Both PSAP and PGRN are pleiotropic proteins that show lipid metabolism modulatory functions and neuroprotective effects in the brain and link to different brain disorders. Therefore, the current thesis aims to decipher the role of PSAP and PGRN in three brain conditions, PD, L-DOPA-induced dyskinesia (LID), and schizophrenia. Regarding PD, in Paper I, we report that PSAP levels correlate mainly with core motor symptoms, while PGRN correlates with non-motor symptoms. In mice, PSAP deficiency in DA neurons (cPSAPDAT) causes behavior defects, DA neurotransmission impairment, and synaptic plasticity disruption. By contrast, mice with PSAP-deficiency in serotonin neurons (cPSAPSERT) show normal behaviors and intact serotonin neurotransmission. Spatial lipidomics unraveled systemic lipid changes in the whole brain, with relation to mitochondrial and peroxisomal functions, in cPSAPDAT mice. On the contrary, cPSAPSERT mice only displayed contained lipid accumulation in the dorsal raphe nucleus (DRN). Metabolic analyses demonstrate that the difference in de novo synthesis of NAD+ between DA and serotonin neurons caused divergent lipid changes in these two mouse lines. cPSAPDAT mice are more vulnerable to α-syn toxicity due to exacerbated aggregation of p-Ser129 α-synuclein that can be reversed by PSAP overexpression, compared to control mice. PSAP overexpression protected wild-type mice against both α-syn- and 6-OHDA-induced toxicity. Consistently, PSAP delivered by encapsulated-cell biodelivery (ECB) devices in the striatum protected rats against α-syn-toxicity. In all, PSAP critically modifies the pathogenesis of PD, especially lipid dyshomeostasis, and serves as a potential therapeutic target for PD. The unfolded protein response (UPR) has long been associated with PD and serves as an important regulator of lipid homeostasis. In Paper II, the unfolded protein response (UPR) related proteins and their transcription levels have been quantitatively confirmed to be changed in PD brains. Meanwhile, UPR is not affected in the periphery of PD patients, which indicates that peripheral UPR is independent of its central counterpart. Regarding LID and schizophrenia, sphingolipid changes have been found in both diseases, and PSAP and PGRN have been genetically linked to schizophrenia. In Paper III and IV, consistent with these facts, PSAP levels are found to be elevated in LID animals. PSAP differentially modulates lipid metabolism in striatal and non-striatal DRD1 neurons and affects basic physiological functions more of the latter. Meanwhile, PSAP deficiency decreases the susceptibility of striatal DRD1 neurons to L-DOPA-induced malfunction that presents as LID. In contrast with PSAP in LID, PSAP and PGRN are decreased in postmortem cingulate tissue from schizophrenia patients. Moreover, PSAP and PGRN downregulation in the cingulate induces widespread brain immediate early gene (IEG) changes and schizophrenic behaviors in mice, which provide evidence for a causative role of PSAP and PGRN in schizophrenia. Therefore, PSAP, together with PGRN, may take part in the pathogenesis of both LID and schizophrenia, though in opposite ways. All in all, this thesis sheds light on the role of PSAP and PGRN in multiple brain disorders and proposes that PSAP and PGRN may serve as a bridge between lipid dyshomeostasis and brain disorders.
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| 2. |
- He, Yachao, et al.
(author)
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Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Journal article (peer-reviewed)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 correlatewith PD-relatedmotor 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.
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| 3. |
- Kaya, Ibrahim, et al.
(author)
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Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson's disease primate model
- 2023
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In: NPJ PARKINSONS DISEASE. - : Springer Nature. - 2373-8057. ; 9:1
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Journal article (peer-reviewed)abstract
- Metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to the neurotoxin MPP+ in the brain causes permanent Parkinson's disease-like symptoms by destroying dopaminergic neurons in the pars compacta of the substantia nigra in humans and non-human primates. However, the complete molecular pathology underlying MPTP-induced parkinsonism remains poorly understood. We used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging to thoroughly image numerous glycerophospholipids and sphingolipids in coronal brain tissue sections of MPTP-lesioned and control non-human primate brains (Macaca mulatta). The results revealed specific distributions of several sulfatide lipid molecules based on chain-length, number of double bonds, and importantly, hydroxylation stage. More specifically, certain long-chain hydroxylated sulfatides with polyunsaturated chains in the molecular structure were depleted within motor-related brain regions in the MPTP-lesioned animals, e.g., external and internal segments of globus pallidus and substantia nigra pars reticulata. In contrast, certain long-chain non-hydroxylated sulfatides were found to be elevated within the same brain regions. These findings demonstrate region-specific dysregulation of sulfatide metabolism within the MPTP-lesioned macaque brain. The depletion of long-chain hydroxylated sulfatides in the MPTP-induced pathology indicates oxidative stress and oligodendrocyte/myelin damage within the pathologically relevant brain regions. Hence, the presented findings improve our current understanding of the molecular pathology of MPTP-induced parkinsonism within primate brains, and provide a basis for further research regarding the role of dysregulated sulfatide metabolism in PD.
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