Metabolic alterations in Parkinson’s disease astrocytes

Abstract

in parkinson`s disease (pD), the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta is associated with Lewy bodies arising from the accumulation of alpha-synuclein protein which leads ultimately to movement impairment. While pD has been considered a disease of the DA neurons, a glial contribution, in particular that of astrocytes, in pD pathogenesis is starting to be uncovered. Here, we report findings from astrocytes derived from induced pluripotent stem cells of LRRK2 G2019S mutant patients, with one patient also carrying a GBA N370S mutation, as well as healthy individuals. the pD patient astrocytes manifest the hallmarks of the disease pathology including increased expression of alpha-synuclein. this has detrimental consequences, resulting in altered metabolism, disturbed ca 2+ homeostasis and increased release of cytokines upon inflammatory stimulation. Furthermore, PD astroglial cells manifest increased levels of polyamines and polyamine precursors while lysophosphatidylethanolamine levels are decreased, both of these changes have been reported also in pD brain. collectively, these data reveal an important role for astrocytes in pD pathology and highlight the potential of ipSc-derived cells in disease modeling and drug discovery. Abbreviations 2-NBDG 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose α-synuclein Alpha synuclein AQP4 Aquaporin 4 Cas9n Nicking Cas9 CI Complex I DA Dopaminergic ECAR Extracellular acidification rate ER Endoplasmic reticulum ESI Electronspray ionization FCCP Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone GBA Glucocerebrocidase GFAP Glial fibrillary acidic protein GLAST Glutamate aspartate transporter 1 GLUT1 Glucose transporter 1 GCase Glucocerebrosidase gRNA Guide RNA HILIC Hydrophilic interaction chromatography IL-1β Interleukin 1 beta IL-6 Interleukin 6 IFNγ Interferon gamma iPSC Induced pluripotent stem cell LCN2 Lipocalin-2

TNF-α and α-synuclein fibrils differently regulate human astrocyte immune reactivity and impair mitochondrial respiration

“…PD-variant-containing astrocytes display increased production of pro-inflammatory cytokines when exposed to aSYN monomers but not when exposed to aSYN fibrils or F110 A recent study suggested that PD astrocytes may show an exacerbated response to pro-inflammatory stressors (Sonninen et al, 2020). We therefore assessed pro-inflammatory cytokine release from astrocytes differentiated from iPSCs generated from PD patients with genetic variants in PARK2, LRRK2, SNCA, or GBA, as well as from patients with idiopathic PD (Figure 3A).…”

Astrocyte-Neuron Metabolic Crosstalk in Neurodegeneration: A Mitochondrial Perspective

“…The secretion to the medium was increased for several polyamines, such as putrescine and spermidine and the levels of their precursors, arginine and ornithine, were elevated in astrocytes. Polyamines are important for various cellular processes, such as cell proliferation and differentiation, gene transcription and translation, as well as regulation of ion channel and receptor activity (119). Notably, changes in polyamine levels were also detected in the cerebrospinal fluid (CSF) of PD patients supporting the relevance of the data obtained in the iPSC models (124).…”

Metabolic and immune dysfunction of glia in neurodegenerative disorders: Focus on iPSC models

“…Our laboratory has demonstrated that PD astrocytes exhibit metabolic abnormalities, disturbed Ca 2+ homeostasis, impaired mitochondrial function, and an increased release of cytokines upon inflammatory stimulation 34 . Increased levels of polyamines and polyamine precursors and decreased levels of lysophosphatidylethanolamine reported in PD astrocytes 34 have also been observed in PD patients 36,37 . The activation of chaperone‐mediated autophagy reduced the toxic effects of PD astrocytes on cocultured neurons in one study (Table 1).…”

“…However, the studies on iPSC‐derived astrocytes carrying PD‐associated mutations LRRK2 G2019S and GBA1 N370S have suggested that PD astrocytes have impaired ability to degrade α‐synuclein 32‐34 and can induce α‐synuclein accumulation, neurite dystrophy, and cell death in cocultured neurons 35 . Our laboratory has demonstrated that PD astrocytes exhibit metabolic abnormalities, disturbed Ca 2+ homeostasis, impaired mitochondrial function, and an increased release of cytokines upon inflammatory stimulation 34 . Increased levels of polyamines and polyamine precursors and decreased levels of lysophosphatidylethanolamine reported in PD astrocytes 34 have also been observed in PD patients 36,37 .…”

“…Healthy human astrocytes rescued the DA neurons exposed to a mitochondrial stressor, rotenone, or potassium cyanide, by restoring the mitochondrial function and dynamics 31 . However, the studies on iPSC‐derived astrocytes carrying PD‐associated mutations LRRK2 G2019S and GBA1 N370S have suggested that PD astrocytes have impaired ability to degrade α‐synuclein 32‐34 and can induce α‐synuclein accumulation, neurite dystrophy, and cell death in cocultured neurons 35 . Our laboratory has demonstrated that PD astrocytes exhibit metabolic abnormalities, disturbed Ca 2+ homeostasis, impaired mitochondrial function, and an increased release of cytokines upon inflammatory stimulation 34 .…”