Epigenetic Regulation of Neuroinflammation in Parkinson's Disease

Abstract

Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson's disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.

Keywords: Parkinson’s disease; astrocytes; epigenetics; microglia; neurodegeneration; neuroinflammation.

Figure 1

Impact of epigenetic mechanisms regulating neuroinflammation in Parkinson’s disease. The neuroinflammation cycle is activated on DA neuron damage, which triggers epigenetic modifications and disturbs the normal function of inflammatory responses. Epigenetic regulators are divided into two categories: neurotoxic and neuroprotective. Neurotoxic epigenetic regulators enhance inflammatory factors and ROS production, transform glial cells to an inflammatory phenotype, and promote dopaminergic neuron death. In contrast, neuroprotective epigenetic regulators display therapeutic characteristics and inhibit neuroinflammation by alleviating DA neuronal damage in Parkinson’s disease.

Figure 2

An overview of synergic epigenetic interactions with neuroinflammatory pathways in PD development. Various epigenetic mechanisms synergistically interact with each other and with inflammatory pathways (MAPK signaling pathway, P13K/Akt/mTOR signaling pathway, JAK/STAT signaling pathway, and NF-κB signaling pathway) to feedforward neuroinflammation in Parkinson’s disease. These neuroinflammatory pathways activate microglia and astrocytes and release inflammatory cytokines. Overactivation of microglia and astrocytes triggers the release of pro-inflammatory cytokines, which further damages normal dopamine neurons, leading to neuronal apoptosis and α-synuclein aggregation. Altogether, these synergic interactions form a vicious cycle that further exaggerates neuroinflammation to hallmark parkinsonism.

Figure 3

The landscape of synergic epigenetic interactions with MAPK signaling pathway in PD development. (A) MAPK signaling pathway is activated due to abnormal accumulation of α-synuclein, which activates glial cells and inflammatory cytokines. (i) Hypomethylation of the intron 1 of SNCA locus dysregulates SNCA gene transcription, leading to abnormal α-synuclein aggregation in the cytoplasm. This allows abnormal α-synuclein to enter the nucleus following oxidative stress and sequester DNMT1 into the cytoplasm, enhancing the hypomethylation of SNCA gene and causing dysregulated transcription. (ii) Meanwhile, HDAC inhibitors cause hyperacetylation of α-synuclein linked histones H2, H3, H4, and p300 promoter region of SNCA to induce α-synuclein aggregation. (iii) Synergic interaction of DNMT1, circSNCA, and cirs-7a suppresses miR-7 expression, which upregulated SNCA gene expression to trigger α-synuclein accumulation. (B) Similarly, LncHOTAIR1 and lncMALAT1 interact with miR-205 to overexpress LRRK2 and activates MAPK signaling pathway. (C) miR-34b/c interacts with PARK2 and DJ-1 to inhibit their neuroprotective role and activates glia cells. miR-494 and miR-4639 downregulate DJ-1 activity and upregulate nitric oxide ten folds to promote neuroinflammation. Moreover, lower expression of PGC-1α also contributes to MAPK signaling pathway activation. Altogether, these epigenetic mechanisms interact with each other and with MAPK signaling pathways to induce neuroinflammation in PD development. Note: ↓ shows downregulated expression, and ↑ shows an upregulated expression.

Figure 4

The landscape of synergic epigenetic interactions with P13K/Akt/mTOR signaling pathway in PD development. P13K/Akt/mTOR signaling pathway is activated due to overexpression of lncRNA UCA 1 and miR-181b, which leads to ROS production and other inflammatory responses. Similarly, CDR1-AS sponge with miR-7 and increases mTOR signaling. Moreover, lower expression of PGC-1α also regulated the inflammatory phenotype of microglia and enhanced P13K/Akt/mTOR pathway signaling. Activated P13K/Akt/mTOR signaling pathway enhances NF-κβ activity that further releases pro-inflammatory cytokines along with iNOS and COX-2. Altogether, these epigenetic mechanisms interact with each other and with P13K/Akt/mTOR signaling pathways to induce neuroinflammation in PD development. Note: ↓ shows downregulated expression, and ↑ shows an upregulated expression.

Figure 5

The landscape of synergic epigenetic interactions with JAK/STAT signaling pathway in PD development. JAK/STAT signaling pathway activation involves multiple epigenetic events. (A) Hyperacetylation of Histone H2, H3, and H4 results in the overexpression of the SNCA gene, which leads to α-synuclein aggregation and JAK/STAT signaling pathway activation. (B) Higher expression of miR-155 and circPTK2 sponging with miR-29b inhibit SOCS1 expression that accelerates neuronal apoptosis through SOCS-1-JAK2/STAT3-IL-1β signaling. (C) Similarly, synergic interaction of lncSNHG1 sponging with miR-7 and lncGAS5 sponging with miR-223-3p activates NLRP3 inflammasome, which transforms glial cells to the inflammatory phenotype and the aggregation of α-synuclein. Moreover, lower expression of PGC-1α also contributes to JAK/STAT signaling pathway activation. Altogether, these epigenetic mechanisms interact with each other and with JAK/STAT signaling pathways to induce neuroinflammation in PD development. Note: ↓ shows downregulated expression, and ↑ shows an upregulated expression.

Figure 6

The landscape of synergic epigenetic interactions with NF-κB signaling pathway in PD development. The NF-κB signaling pathway is activated on the higher level of α-synuclein deposits. (A) Increased histone H3 acetylation overexpresses the SNCA gene and increases the release of inflammatory cytokines. (B) Similarly, coordination of lncMALAT1 sponging with miR-124 and MEKK3 also enhances NF-κB signaling pathway activation. (C) Hypomethylation of IL-β displayed similar neuroinflammatory effects. Moreover, lower expression of PGC-1α also contributes to NF-κB signaling pathway activation. Altogether, these epigenetic mechanisms interact with each other and with NF-κB signaling pathways to induce neuroinflammation in PD development. Note: ↓ shows downregulated expression, and ↑ shows an upregulated expression.

Figure 7

Proposed applications of neurotoxic and neuroprotective epigenetic modification in Parkinson’s disease management. Neurotoxic epigenetic modifications can be utilized for PD diagnosis. In contrast, neuroprotective epigenetic modifications can be utilized for PD therapeutics.