Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 31, 2024

Abstract In brain, the striatum is a heterogenous region involved in reward and goal-directed behaviors. Striatal dysfunction linked to psychiatric disorders, including opioid use disorder (OUD). subregions are divided based on neuroanatomy, each with unique roles OUD. OUD, dorsal altered processing, formation of habits, development negative affect during withdrawal. Using single nuclei RNA-sequencing, we identified both canonical (e.g., dopamine receptor subtype) less abundant cell populations interneurons) human striatum. Pathways related neurodegeneration, interferon response, DNA damage were significantly enriched striatal neurons individuals markers also elevated opioid-exposed rhesus macaques. Sex-specific molecular differences glial subtypes associated chronic stress found particularly female individuals. Together, describe different types identify type-specific alterations

Язык: Английский

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

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Июль 2, 2024

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

Язык: Английский

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Aging, cellular senescence and Parkinson's disease

Journal of Parkinson s Disease, Год журнала: 2025, Номер unknown

Опубликована: Фев. 2, 2025

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1–2% of people over age 65. The risk developing PD dramatically increases with advanced age, indicating that aging likely a driving factor in neuropathogenesis. Several age-associated biological changes are also hallmarks neuropathology, including mitochondrial dysfunction, oxidative stress, and neuroinflammation. Accumulation senescent cells an important feature contributes to age-related diseases. How cellular senescence affects brain health whether this phenomenon neuropathogenesis not yet fully understood. In review, we highlight aging, loss proteostasis, genomic instability telomere attrition relation well established neuropathological pathways. We then discuss context neuroscience review studies directly examine PD. Studying presents challenges holds promise for advancing our understanding mechanisms, which could contribute development effective disease-modifying therapeutics. Targeting or modulating senescence-associated secretory phenotype (SASP) requires comprehensive complex relationship between pathogenesis senescence.

Язык: Английский

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Aberrant accumulation of phosphorylated BRCA1 in brainstem-type and cortical-type Lewy bodies in Lewy body disease

Journal of Neuropathology & Experimental Neurology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

BRCA1 plays important roles in several biological events during the DNA damage response (DDR). We aimed to determine whether cytoplasmic accumulation of or its phosphorylated form, pBRCA1, is specific inclusions tauopathies, if it also occurs α-synuclein-positive Lewy body disease (LBD). Using brain tissue from pure LBD, LBD with Alzheimer (AD) co-pathology (LBD-AD), and control cases, immunohistochemical distributions BRCA1, binding partner BARD1, 53BP1 were examined. The results showed that pBRCA1 (Ser1423) BARD1 accumulated brainstem-type bodies (LBs), whereas only was present cortical-type LBs. There no significant difference frequency (Ser1423)-positive LBs between LBD-AD cases. minimally detected neuronal nuclei controls absent In 53BP1-immunoreactive deposits nuclei. Thus, DDR dysfunction due sequestration may play a role pathogenesis. Additionally, selective LBs, but not points distinct mechanisms formation these inclusion types, offering further insights into pathology.

Язык: Английский

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Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(11)

Опубликована: Окт. 30, 2023

Abstract Arsenic and antimony are metalloids with profound effects on biological systems human health. Both elements toxic to cells organisms, exposure is associated several pathological conditions including cancer neurodegenerative disorders. At the same time, arsenic- antimony-containing compounds used in treatment of multiple diseases. Although these can both cause cure disease, their modes molecular action incompletely understood. The past decades have seen major advances our understanding arsenic toxicity, emphasizing genotoxicity proteotoxicity as key contributors pathogenesis. In this review, we highlight mechanisms by which focusing genotoxic proteotoxic effects. maintain proteostasis during metalloid also described. Furthermore, address how metalloid-induced may promote disease be interrelated together contribute proteinopathies. A deeper cellular toxicity response links pathogenesis development strategies for prevention treatment.

Язык: Английский

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Base excision repair and double strand break repair cooperate to modulate the formation of unrepaired double strand breaks in mouse brain

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 4, 2024

Язык: Английский

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Defective DNA Repair: A Putative Nexus Linking Immunological Diseases, Neurodegenerative Disorders, and Cancer

Mutagenesis, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

DNA damage is a common event in cells, resulting from both internal and external factors. The maintenance of genomic integrity vital for cellular function physiological processes. inadequate repair results the instability, which has been associated with development progression various human diseases. Accumulation can lead to multiple diseases, such as neurodegenerative disorders, cancers, immune deficiencies, infertility aging. This comprehensive review delves impact alterations response genes (DDR) tries elucidate how what extent same traits modulate diverse major cancer, immunological disorders. DDR apparently trait connecting important complex disorders humans. However, pathogenesis above diseases are different leading divergent consequences. It discover switch(es) that direct further pathogenic process either proliferative, or degenerative Our understanding influence on may enable strategies prevent, diagnose, treat these In our article, we analysed publicly available GWAS summary statistics NHGRI-EBI Catalog identified 12,009 single nucleotide polymorphisms (SNPs) cancer. Among these, 119 SNPs were found pathways, exhibiting significant p-values. Additionally, 44 linked cancer types (NDDs), including four located DDR-related genes: ATM, CUX2, WNT3. Furthermore, 402 two gene RAD51B. highlights versatility pathway multifactorial specific mechanisms regulate initiate distinct processes remain be elucidated.

Язык: Английский

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Novel Insights into Parkin–Mediated Mitochondrial Dysfunction and “Mito-Inflammation” in α-Synuclein Toxicity. The Role of the cGAS–STING Signalling Pathway

Journal of Inflammation Research, Год журнала: 2024, Номер Volume 17, С. 4549 - 4574

Опубликована: Июль 1, 2024

Abstract: The prevalence of age-related neurodegenerative diseases, such as Parkinson's disease (PD) and related disorders continues to grow worldwide. Increasing evidence links intracellular inclusions misfolded alpha-synuclein (α-syn) aggregates, so-called Lewy bodies (LB) neuritis, the progressive pathology PD other synucleinopathies. Our previous findings established that α-syn oligomers induce S-nitrosylation deregulation E3-ubiquitin ligase Parkin, leading mitochondrial disturbances in neuronal cells. accumulation damaged mitochondria a consequence, together with release mitochondrial-derived damage-associated molecular patterns (mtDAMPs) could activate innate immune response neuroinflammation ("mito-inflammation"), eventually accelerating neurodegeneration. However, pathways transmit pro-inflammatory signals from are not well understood. One proposed be cyclic GMP-AMP synthase (cGAS) – stimulator interferon genes (STING) (cGAS–STING) pathway, which plays pivotal role modulating response. It has recently been suggested cGAS–STING may contribute development various pathological conditions. Especially, its excessive engagement lead appear essential for brain including PD. precise mechanisms underlying pathway activation synucleinopathies fully This review focuses on linking dysfunction these disorders, particularly emphasizing signaling. We propose critical driver inflammation α-syn-dependent neurodegeneration hypothesize cGAS–STING–driven "mito-inflammation" one key promoting Understanding α-syn–induced cGAS–STING–associated identification new targets treatment disorders. Keywords: α-synuclein, mtDAMPs, mito-inflammation, sterile inflammation,

Язык: Английский

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

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(22), С. 16129 - 16129

Опубликована: Ноя. 9, 2023

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

Язык: Английский

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Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(10), С. 8651 - 8651

Опубликована: Май 12, 2023

DNA damage and defective repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that PD-associated protein DJ-1 plays an essential role modulating double-strand break (DSB) repair. Specifically, is a response (DDR) can be recruited sites, where it promotes DSB through both homologous recombination nonhomologous end joining. Mechanistically, interacts directly with PARP1, nuclear enzyme for genomic stability, stimulates its enzymatic activity during Importantly, cells from PD patients mutation also have PARP1 impaired of DSBs. In summary, our findings uncover novel function genome stability maintenance, suggest may contribute pathogenesis mutations.

Язык: Английский

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