Abstract:Parkinson's disease (PD) is a systemic neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and stooping posture. When more than 60% of dopaminergic neurons in the substantia nigra of the brain have died, motor symptoms manifest in PD. Currently, oxidative stress (OS) is considered to be one of the leading factors provoking death of dopaminergic neurons in PD. This review is concerned with the role of polyamines in PD, especially focusing on their role in OS induction. Polyamines (putresc… Show more
“…6A,B). Altered polyamine 23 and phospholipids 24 levels have been previously linked to Parkinsons and our results show that the PD astrocytes manifest these known metabolic alterations.…”
Section: Resultssupporting
confidence: 73%
“…6 A,B). Altered polyamine 23 and phospholipids 24 levels have been previously linked to Parkinsons and our results show that the PD astrocytes manifest these known metabolic alterations. Figure 6 Non-targeted metabolite profiling of astrocytes revelaled several statistically significantly differentiating compounds in cell lysates ( A ) and media ( B ) of healthy and PD astrocytes analyzed by UHPLC-QTOF-MS.…”
Section: Resultssupporting
confidence: 73%
“…Further, polyamines have been shown to enhance α-synuclein toxicity and increase α-synuclein aggregation 41 . Inflammation and stress can stimulate polyamine accumulation in glia, elevating their levels and the levels of their breakdown products 42 and prolonged elevation of polyamine levels has been suggested to lead to gliosis 23 . We detected increased secretion of putrescine and spermidine to the media from the PD astrocytes as well as increased polyamine precursor, arginine and ornithine, levels in the astrocytes themselves without any inflammatory stimulation, suggesting that either the PD astrocytes manifest an innate defect in polyamine metabolism or some cell intrinsic stress response is stimulating polyamine production in PD astrocytes.…”
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
“…6A,B). Altered polyamine 23 and phospholipids 24 levels have been previously linked to Parkinsons and our results show that the PD astrocytes manifest these known metabolic alterations.…”
Section: Resultssupporting
confidence: 73%
“…6 A,B). Altered polyamine 23 and phospholipids 24 levels have been previously linked to Parkinsons and our results show that the PD astrocytes manifest these known metabolic alterations. Figure 6 Non-targeted metabolite profiling of astrocytes revelaled several statistically significantly differentiating compounds in cell lysates ( A ) and media ( B ) of healthy and PD astrocytes analyzed by UHPLC-QTOF-MS.…”
Section: Resultssupporting
confidence: 73%
“…Further, polyamines have been shown to enhance α-synuclein toxicity and increase α-synuclein aggregation 41 . Inflammation and stress can stimulate polyamine accumulation in glia, elevating their levels and the levels of their breakdown products 42 and prolonged elevation of polyamine levels has been suggested to lead to gliosis 23 . We detected increased secretion of putrescine and spermidine to the media from the PD astrocytes as well as increased polyamine precursor, arginine and ornithine, levels in the astrocytes themselves without any inflammatory stimulation, suggesting that either the PD astrocytes manifest an innate defect in polyamine metabolism or some cell intrinsic stress response is stimulating polyamine production in PD astrocytes.…”
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
“…On the contrary, the increased levels of cadaverine match well with an overgrown Escherichia population; the bacteria in the human gut that can produce this biogenic amine [ 58 ]. It has been suggested that dysregulation of cadaverine can be involved in neurodegeneration and the formation of Lewy bodies in PD [ 59 , 60 ]. In vitro studies highlighted that biogenic amines can bind the N-terminal region of the amyloid beta peptide, significantly increasing the aggregation of α-synuclein [ 61 ].…”
Parkinson’s disease (PD) is a clinically heterogenic disorder characterized by distinct clinical entities. Most studies on motor deficits dichotomize PD into tremor dominant (TD) or non-tremor dominant (non-TD) with akinetic-rigid features (AR). Different pathophysiological mechanisms may affect the onset of motor manifestations. Recent studies have suggested that gut microbes may be involved in PD pathogenesis. The aim of this study was to investigate the gut microbiota and metabolome composition in PD patients in relation to TD and non-TD phenotypes. In order to address this issue, gut microbiota and the metabolome structure of PD patients were determined from faecal samples using 16S next generation sequencing and gas chromatography–mass spectrometry approaches. The results showed a reduction in the relative abundance of Lachnospiraceae, Blautia, Coprococcus, Lachnospira, and an increase in Enterobacteriaceae, Escherichia and Serratia linked to non-TD subtypes. Moreover, the levels of important molecules (i.e., nicotinic acid, cadaverine, glucuronic acid) were altered in relation to the severity of phenotype. We hypothesize that the microbiota/metabolome enterotypes associated to non-TD subtypes may favor the development of gut inflammatory environment and gastrointestinal dysfunctions and therefore a more severe α-synucleinopathy. This study adds important information to PD pathogenesis and emphasizes the potential pathophysiological link between gut microbiota/metabolites and PD motor subtypes.
“…Parkinson's disease is a progressiv e disorder characterized by various motor-related symptoms, including slow movements, body tremors, and rigidity [131,132]. In general, motor symptoms related to PD irst manifest after the death of over 60% of dopaminergic neurons within the brain [133,134]. Indeed, the pathological hallmarks of PD include the generation of Lewy bodies and the erosion of dopaminergic neurons in the substantia nigra pars compacta [135][136][137].…”
Vitamin E Antioxidant, Neuroprotection Vitamin E is a scavenger of several ROS and serves to reduce their reactivity and toxicity. It offers protection from the propagative damage of ROS by inhibiting the oxidative modifi cation of lipoproteins AD [74-79,82-86] PD [175-177,79] ALS [193,217,218] Vitamin C Antioxidant, Neuroprotection Vitamin C is an excellent antioxidant, suitable in reducing ROS levels, lipid peroxidation, and oxidative stress. It is also useful in regenerating other antioxidants. AD [81,82,75,77,79] PD [166-168] ALS [213,214] Vitamin D Antioxidant Neuroprotection Vitamin D prevent oxidative stress, lower the production of free radicals, and reduce neurotoxicity through the enhancement of autophagy signaling pathways AD [74-78,30,16,80] PD [157-159,169-174] ALS [215,216] Vitamin A Antioxidan Vitamin A prevent the formation of Aβ plaques AD [16,30,74-78] Vitamin B Antioxidant Neuroprotection Vitamin B perform antioxidant and neuroprotective functions AD [88-90] PD [157-159,162-165] HD [105] Curcumin Antioxidant Anti-infl ammatory Neuroprotection Curcumin is a scavenger of free radicals and reduces mitochondrial disfunction. AD [100,101] Omega−3 fatty acids Antioxidant Anti-infl ammatory Omega-3 fatty acids reduce ROS formation acting as free radical scavengers.
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