DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

Wang, Zhong-Xuan; Li, Yaolin; Pu, Jiali; Zhang, Baorong

doi:10.3390/ijms24076313

Cited by 16 publications

(12 citation statements)

References 223 publications

(369 reference statements)

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“…2 Gi). The analysis pointed to a decrease in stress-responsive functions, including pathways associated with the DNA damage response, in accordance with recent work highlighting the importance of DNA repair and other stress-response mechanisms in PD [ 44 ]. Downregulated pathways were enriched in glial cells, most prominently within the Micro1 and OPC1 clusters, including immune response pathways specific to microglia (Fig.…”

Section: Resultssupporting

confidence: 86%

Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks

Shwab,

Gingerich,

Man

et al. 2024

acta neuropathol commun

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The genetic architecture of Parkinson’s disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

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Section: Resultssupporting

confidence: 86%

Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks

Shwab,

Gingerich,

Man

et al. 2024

acta neuropathol commun

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“…None of the treatments, except 6-ODHA, induced DNA damage, measured via 8-OHdG. This biomarker evaluates oxidative DNA damage and PD progression [50][51][52]. This response suggests that metal-generated oxidative damage is not significant enough to lead to permanent DNA damage at this exposure timepoint.…”

Section: Discussionmentioning

confidence: 97%

Evaluating Manganese, Zinc, and Copper Metal Toxicity on SH-SY5Y Cells in Establishing an Idiopathic Parkinson’s Disease Model

Pradhan,

Liu,

Sayes

2023

IJMS

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Parkinson’s disease (PD) is a neurodegenerative condition marked by loss of motor coordination and cognitive impairment. According to global estimates, the worldwide prevalence of PD will likely exceed 12 million cases by 2040. PD is primarily associated with genetic factors, while clinically, cases are attributed to idiopathic factors such as environmental or occupational exposure. The heavy metals linked to PD and other neurodegenerative disorders include copper, manganese, and zinc. Chronic exposure to metals induces elevated oxidative stress and disrupts homeostasis, resulting in neuronal death. These metals are suggested to induce idiopathic PD in the literature. This study measures the effects of lethal concentration at 10% cell death (LC10) and lethal concentration at 50% cell death (LC50) concentrations of copper, manganese, and zinc chlorides on SH-SY5Y cells via markers for dopamine, reactive oxygen species (ROS) generation, DNA damage, and mitochondrial dysfunction after a 24 h exposure. These measurements were compared to a known neurotoxin to induce PD, 100 µM 6-hydroxydopamine (6-ODHA). Between the three metal chlorides, zinc was statistically different in all parameters from all other treatments and induced significant dopaminergic loss, DNA damage, and mitochondrial dysfunction. The LC50 of manganese and copper had the most similar response to 6-ODHA in all parameters, while LC10 of manganese and copper responded most like untreated cells. This study suggests that these metal chlorides respond differently from 6-ODHA and each other, suggesting that idiopathic PD utilizes a different mechanism from the classic PD model.

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“…HSPA1, also known as Hsp70, has been found to be released from damaged cells, acting as a local danger signal ( Giuliano et al, 2011 ). Both SIRT4 and RAD52 have received attention for their therapeutic effects on DNA damage, which has been found to induce inflammatory responses in several neuronal cell types ( Wang et al, 2021 , 2023 ). Although these genes have contradictory effects, neuroinflammation induces damage to nerve tissues while promoting the activation of neuroprotective mechanisms ( Gelders et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of plasma and substantia nigra in Parkinson’s disease: unraveling biomarkers and insights from the lncRNA–miRNA–mRNA ceRNA network

Chun,

Kim

2024

Front. Aging Neurosci.

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IntroductionParkinson’s disease (PD) is a rapidly growing neurological disorder characterized by diverse movement symptoms. However, the underlying causes have not been clearly identified, and accurate diagnosis is challenging. This study aimed to identify potential biomarkers suitable for PD diagnosis and present an integrative perspective on the disease.MethodsWe screened the GSE7621, GSE8397-GPL96, GSE8397-GPL97, GSE20163, and GSE20164 datasets in the NCBI GEO database to identify differentially expressed (DE) mRNAs in the substantia nigra (SN). We also screened the GSE160299 dataset from the NCBI GEO database to identify DE lncRNAs and miRNAs in plasma. We then constructed 2 lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) regulatory networks based on the ceRNA hypothesis. To understand the biological function, we performed Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses for each ceRNA network. The receiver operating characteristic analyses (ROC) was used to assess ceRNA results.ResultsWe identified 7 upregulated and 29 downregulated mRNAs as common DE mRNAs in the 5 SN datasets. In the blood dataset, we identified 31 DE miRNAs (9 upregulated and 22 downregulated) and 332 DE lncRNAs (69 upregulated and 263 downregulated). Based on the determined interactions, 5 genes (P2RX7, HSPA1, SLCO4A1, RAD52, and SIRT4) appeared to be upregulated as a result of 10 lncRNAs sponging 4 miRNAs (miR-411, miR-1193, miR-301b, and miR-514a-2/3). Competing with 9 genes (ANK1, CBLN1, RGS4, SLC6A3, SYNGR3, VSNL1, DDC, KCNJ6, and SV2C) for miR-671, a total of 26 lncRNAs seemed to function as ceRNAs, influencing genes to be downregulated.DiscussionIn this study, we successfully constructed 2 novel ceRNA regulatory networks in patients with PD, including 36 lncRNAs, 5 miRNAs, and 14 mRNAs. Our results suggest that these plasma lncRNAs are involved in the pathogenesis of PD by sponging miRNAs and regulating gene expression in the SN of the brain. We propose that the upregulated and downregulated lncRNA-mediated ceRNA networks represent mechanisms of neuroinflammation and dopamine neurotransmission, respectively. Our ceRNA network, which was associated with PD, suggests the potential use of DE miRNAs and lncRNAs as body fluid diagnostic biomarkers. These findings provide an integrated view of the mechanisms underlying gene regulation and interactions in PD.

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DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

Cited by 16 publications

References 223 publications

Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks

Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks

Evaluating Manganese, Zinc, and Copper Metal Toxicity on SH-SY5Y Cells in Establishing an Idiopathic Parkinson’s Disease Model

Integrative analysis of plasma and substantia nigra in Parkinson’s disease: unraveling biomarkers and insights from the lncRNA–miRNA–mRNA ceRNA network

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