Dataset Information

Astrocytes expressing Vitamin D-activating enzyme identify Parkinson's disease.

ABSTRACT:

Introduction

Astrocytes are involved in Parkinson's disease (PD) where they could contribute to α-Synuclein pathology but also to neuroprotection via α-Synuclein clearance. The molecular signature underlying their dual role is still elusive. Given that vitamin D has been recently suggested to be protective in neurodegeneration, the aim of our study was to investigate astrocyte and neuron vitamin D pathway alterations and their correlation with α-Synuclein aggregates (ie, oligomers and fibrils) in human brain obtained from PD patients.

Methods

The expression of vitamin D pathway components CYP27B1, CYP24A1, and VDR was examined in brains obtained from PD patients (Braak stage 6; n = 9) and control subjects (n = 4). We also exploited proximity ligation assay to identified toxic α-Synuclein oligomers in human astrocytes.

Results

We found that vitamin D-activating enzyme CYP27B1 identified a subpopulation of astrocytes exclusively in PD patients. CYP27B1 positive astrocytes could display neuroprotective features as they sequester α-Synuclein oligomers and are associated with Lewy body negative neurons.

Conclusion

The presence of CYP27B1 astrocytes distinguishes PD patients and suggests their contribution to protect neurons and to ameliorate neuropathological traits.

SUBMITTER: Mazzetti S

PROVIDER: S-EPMC8981451 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Astrocytes expressing Vitamin D-activating enzyme identify Parkinson's disease.

Mazzetti Samanta S Barichella Michela M Giampietro Federica F Giana Angelica A Calogero Alessandra M AM Amadeo Alida A Palazzi Nicola N Comincini Alessandro A Giaccone Giorgio G Bramerio Manuela M Caronni Serena S Cereda Viviana V Cereda Emanuele E Cappelletti Graziella G Rolando Chiara C Pezzoli Gianni G

CNS neuroscience & therapeutics 20220215 5

<h4>Introduction</h4>Astrocytes are involved in Parkinson's disease (PD) where they could contribute to α-Synuclein pathology but also to neuroprotection via α-Synuclein clearance. The molecular signature underlying their dual role is still elusive. Given that vitamin D has been recently suggested to be protective in neurodegeneration, the aim of our study was to investigate astrocyte and neuron vitamin D pathway alterations and their correlation with α-Synuclein aggregates (ie, oligomers and fi ...[more]

PMID: 35166042

Similar Datasets

Project description:IntroductionA recent approach to cure neurodegenerative diseases is to reprogram fibroblasts into functioning neurons using multiple exogenous transcription factors (TFs) and micro-RNAs. Administering agents that can endogenously induce these TFs may bypass the limitations of this approach. Astrocytes may represent a part of the extrahepatic-stellate system involved in vitamin-A (VA ) homeostasis. Activated-stellate cells lose their VA -storage capacity, and this was previously applied for hepatic-stellate cells (HSCs) targeting to treat liver fibrosis. Accordingly, it is hypothesized that Parkinson's disease (PD) may be coupled with retinoid depletion that may extract VA from VA -rich-HSCs triggering liver fibrosis. Thus, VA administration may selectively target VA -deficient reactive astrocytes and HSCs. Besides, VA has the regenerative capability and may induce endogenous-TFs generation.MethodsFluorescently labeled VA -coupled liposomes (FLV) were traced using confocal laser microscope in rats with induced PD for detecting brain accumulation and uptake into fluorescently labeled astrocytes. Liver fibrosis associated with PD was assessed biochemically and histopathologically, while VA deficiency was confirmed by assessing retinol-binding protein gene expression in the brain and liver. Multiple VA doses were tested for reversing PD-associated liver fibrosis, generating TFs (involved in reprograming astrocytes/fibroblasts into different neuronal types) and capability of dopaminergic-neurons regeneration.ResultsFluorescently labeled VA -coupled liposomes revealed selective brain accumulation and uptake into astrocytes. PD was associated with significant liver fibrosis and VA deficiency in the brain and liver. Furthermore, VA -medium dose (VAMD) was the optimum one for reversing PD-associated liver fibrosis, generating multiple astrocytes/fibroblasts reprogramming TFs, regenerating dopaminergic neurons, and improving PD.ConclusionVA -medium dose pursued brain targeting in PD with the potential capability of regenerating neurons and restoring dopaminergic transmission. This may place this therapy as an essential treatment in PD management protocol.

Project description:While astrocytes, the most abundant cells found in the brain, have many diverse functions, their role in the lysosomal storage disorder Gaucher disease (GD) has not been explored. GD, resulting from the inherited deficiency of the enzyme glucocerebrosidase and subsequent accumulation of glucosylceramide and its acylated derivative glucosylsphingosine, has both non-neuronopathic (GD1) and neuronopathic forms (GD2 and 3). Furthermore, mutations in GBA1, the gene mutated in GD, are an important risk factor for Parkinson's disease (PD). To elucidate the role of astrocytes in the disease pathogenesis, we generated iAstrocytes from induced pluripotent stem cells made from fibroblasts taken from controls and patients with GD1, with and without PD. We also made iAstrocytes from an infant with GD2, the most severe and progressive form, manifesting in infancy. Gaucher iAstrocytes appropriately showed deficient glucocerebrosidase activity and levels and substrate accumulation. These cells exhibited varying degrees of astrogliosis, Glial Fibrillary Acidic Protein (GFAP) up-regulation and cellular proliferation, depending on the level of residual glucocerebrosidase activity. Glutamte uptake assays demonstrated that the cells were functionally active, although the glutamine transporter EEAT2 was upregulated and EEAT1 downregulated in the GD2 samples. GD2 iAstrocytes were morphologically different, with severe cytoskeletal hypertrophy, overlapping of astrocyte processes, pronounced up-regulation of GFAP and S100β, and significant astrocyte proliferation, recapitulating the neuropathology observed in patients with GD2. Although astrocytes do not express α-synuclein, when the iAstrocytes were co-cultured with dopaminergic neurons generated from the same iPSC lines, excessive α-synuclein released from neurons was endocytosed by astrocytes, translocating into lysosomes. Levels of aggregated α-synuclein increased significantly when cells were treated with monomeric or fibrillar α-synuclein. GD1-PD and GD2 iAstrocytes also exhibited impaired Cathepsin D activity, leading to further α-synuclein accumulation. Cytokine and chemokine profiling of the iAstrocytes demonstrated an inflammatory response. Thus, in patients with GBA1-associated parkinsonism, astrocytes appear to play a role in α-synuclein accumulation and processing, contributing to neuroinflammation.

Dataset Information

Astrocytes expressing Vitamin D-activating enzyme identify Parkinson's disease.

Introduction

Methods

Results

Conclusion

Publications

Astrocytes expressing Vitamin D-activating enzyme identify Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets