Epigenetic Modifications of the <i>α</i>‐Synuclein Gene and Relative Protein Content Are Affected by Ageing and Physical Exercise in Blood from Healthy Subjects

Daniele, Simona; Costa, Barbara; Pietrobono, Deborah; Giacomelli, Chiara; Iofrida, Caterina; Trincavelli, Maria Letizia; Fusi, Jonathan; Franzoni, Ferdinando; Martini, Claudia

doi:10.1155/2018/3740345

Cited by 22 publications

(15 citation statements)

References 77 publications

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“…In both the WT and GFAP.HMOX1 mice, we observed a progressive decline in serum miR‐153 and miR‐223 concentrations between 11 and 19 months of age. These findings correlate with age‐related increases in nigrostriatal and peripheral α‐synuclein expression reported in humans and monkeys (Barbour et al, ; Chu & Kordower, ; Daniele et al, ; Daniele et al, ; Matsumoto et al, ). miR‐153 levels were significantly lower in GFAP.HMOX1 serum than WT serum at each time point surveyed, suggesting that miR‐153, more so than miR‐223, may be responsible for upregulation of peripheral α‐synuclein expression under pathological (parkinsonian) conditions.…”

Section: Discussionsupporting

confidence: 80%

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

Cressatti

Song

Turk

et al. 2019

Glia

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α‐Synuclein is a key player in the pathogenesis of Parkinson disease (PD). Expression of human heme oxygenase‐1 (HO‐1) in astrocytes of GFAP.HMOX1 transgenic (TG) mice between 8.5 and 19 months of age results in a parkinsonian phenotype characterized by neural oxidative stress, nigrostriatal hypodopaminergia associated with locomotor incoordination, and overproduction of α‐synuclein. We identified two microRNAs (miR‐), miR‐153 and miR‐223, that negatively regulate α‐synuclein in the basal ganglia of male and female GFAP.HMOX1 mice. Serum concentrations of both miRNAs progressively declined in the wild‐type (WT) and GFAP.HMOX1 mice between 11 and 19 months of age. Moreover, at each time point surveyed, circulating levels of miR‐153 were significantly lower in the TG animals compared to WT controls, while α‐synuclein protein concentrations were elevated in erythrocytes of the GFAP.HMOX1 mice at 19 months of age relative to WT values. Primary WT neurons co‐cultured with GFAP.HMOX1 astrocytes exhibited enhanced protein oxidation, mitophagy and apoptosis, aberrant expression of genes regulating the dopaminergic phenotype, and an imbalance in gene expression profiles governing mitochondrial fission and fusion. Many, but not all, of these neuronal abnormalities were abrogated by small interfering RNA (siRNA) knockdown of α‐synuclein, implicating α‐synuclein as a potent, albeit partial, mediator of HO‐1's neurodystrophic effects in these parkinsonian mice. Overexpression of HO‐1 in stressed astroglia has previously been documented in the substantia nigra of idiopathic PD and may promote α‐synuclein production and toxicity by downmodulating miR‐153 and/or miR‐223 both within the CNS and in peripheral tissues.

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Section: Discussionsupporting

confidence: 80%

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

Cressatti

Song

Turk

et al. 2019

Glia

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“…PD is characterized by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra and the presence of proteinaceous inclusions known as Lewy bodies, which are composed of α Syn [18]. Despite intensive studies, the cause of neuronal loss in PD and the presence of protein inclusions remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway

Feng

Zheng

Zhang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Evidence suggests that various forms of α-synuclein- (αSyn-) mediated microglial activation are associated with the progression of Parkinson’s disease. MicroRNA-155-5p (miR155-5p) is one of the most important microRNAs and enables a robust inflammatory response. Triptolide (T10) is a natural anti-inflammatory component, isolated from a traditional Chinese herb. The objective of the current study was to identify the role and potential regulatory mechanism of T10 in αSyn-induced microglial activation via the miR155-5p mediated SHIP1 signaling pathway. Mouse primary microglia were exposed to monomers, oligomers, and preformed fibrils (PFFs) of human wild-type αSyn, respectively. The expressions of TNFα and IL-1β, measured by enzyme-linked immunosorbent assay (ELISA) and qPCR, demonstrated that PFFs initiated the strongest immunogenicity in microglia. Application of inhibitors of toll-like receptor (TLR) 1/2, TLR4, and TLR9 indicated that PFFs activated microglia mainly via the NF-κB pathway by binding TLR1/2 and TLR4. Treatment with T10 significantly suppressed PFF-induced microglial activation and attenuated the release of proinflammatory cytokines including TNFα and IL-1β. Levels of IRAK1, TRAF6, IKKα/β, p-IKKα/β, NF-κB, p-NF-κB, PI3K, p-PI3K, t-Akt, p-Akt and SHIP1 were measured via Western blot. Levels of miR155-5p were measured by qPCR. The results demonstrated that SHIP1 acted as a downstream target molecule of miR155-5p. Treatment with T10 did not alter the expression of IRAK1 and TRAF6, but significantly decreased the expression of miR155-5p, resulting in upregulation of SHIP1 and repression of NF-κB activity, suggesting inhibition of inflammation and microglial activation. The protective effects of T10 were abolished by the use of SHIP1 siRNA and its inhibitor, 3AC, and miR155-5p mimics. In conclusion, our results demonstrated that treatment with T10 suppressed microglial activation and attenuated the release of proinflammatory cytokines by suppressing NF-κB activity via targeting the miR155-5p/SHIP1 pathway in PFFs-induced microglial activation.

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“…Indeed, RBCs are highly susceptible to oxidative damage, due to the high concentration of oxygen and haemoglobin [17, 18]. Moreover, recent findings have shown an accumulation of ND-related proteins in these cells and its relationship with NDs [11, 19–21]. In particular, the presence of misfolded proteins ( α -syn, A β , and tau) and their aggregates ( α -syn-A β and α -syn-tau) has been recently proved in RBCs from healthy subjects and patients with NDs [5, 10, 11, 22].…”

Section: Introductionmentioning

confidence: 99%

High Levels of β-Amyloid, Tau, and Phospho-Tau in Red Blood Cells as Biomarkers of Neuropathology in Senescence-Accelerated Mouse

Piccarducci

Pietrobono

Pellegrini

et al. 2019

Oxidative Medicine and Cellular Longevity

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Alzheimer’s Disease (AD) is the most common Neurodegenerative Disease (ND), primarily characterised by neuroinflammation, neuronal plaques of β-amyloid (Aβ), and neurofibrillary tangles of hyperphosphorylated tau. α-Synuclein (α-syn) and its heteroaggregates with Aβ and tau have been recently included among the neuropathological elements of NDs. These pathological traits are not restricted to the brain, but they reach peripheral fluids as well. In this sense, Red Blood Cells (RBCs) are emerging as a good model to investigate the biochemical alterations of aging and NDs. Herein, the levels of homo- and heteroaggregates of ND-related proteins were analysed at different stages of disease progression. In particular, a validated animal model of AD, the SAMP8 (Senescence-Accelerated Mouse-Prone) and its control strain SAMR1 (Senescence-Accelerated Mouse-Resistant) were used in parallel experiments. The levels of the aforementioned proteins and of the inflammatory marker interleukin-1β (IL-1β) were examined in both brain and RBCs of SAMP8 and SAMR1 at 6 and 8 months. Brain Aβ, tau, and phospho-tau (p-tau) were higher in SAMP8 mice than in control mice and increased with AD progression. Similar accumulation kinetics were found in RBCs, even if slower. By contrast, α-syn and its heterocomplexes (α-syn-Aβ and α-syn-tau) displayed different accumulation kinetics between brain tissue and RBCs. Both brain and peripheral IL-1β levels were higher in SAMP8 mice, but increased sooner in RBCs, suggesting that inflammation might initiate at a peripheral level before affecting the brain. In conclusion, these results confirm RBCs as a valuable model for monitoring neurodegeneration, suggesting peripheral Aβ, tau, and p-tau as potential early biomarkers of AD.

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Epigenetic Modifications of the α‐Synuclein Gene and Relative Protein Content Are Affected by Ageing and Physical Exercise in Blood from Healthy Subjects

Cited by 22 publications

References 77 publications

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway

High Levels of β-Amyloid, Tau, and Phospho-Tau in Red Blood Cells as Biomarkers of Neuropathology in Senescence-Accelerated Mouse

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