Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK

Liu, Ying; Yu, Lijia; Xu, Yaling; Tang, Xiaohui; Wang, Xijin

doi:10.1186/s12974-020-02023-9

Cited by 10 publications

(6 citation statements)

References 79 publications

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“…TGF-β2 haplodeficiency (Tgfb2 +/-) mice have fewer DA neurons in the SN and a significantly reduced dopamine concentration in the striatum in adulthood [204]. Smad3 and pSmad3 expression decreases with age in mouse substantia nigra [205]. Smad3-deficient mice develop a progressive loss of DA neurons and aggregation of α-synuclein [206].…”

Section: Parkinson's Diseasementioning

confidence: 99%

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Luo

2022

Biomedicines

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Astrocytes are essential for normal brain development and functioning. They respond to brain injury and disease through a process referred to as reactive astrogliosis, where the reactivity is highly heterogenous and context-dependent. Reactive astrocytes are active contributors to brain pathology and can exert beneficial, detrimental, or mixed effects following brain insults. Transforming growth factor-β (TGF-β) has been identified as one of the key factors regulating astrocyte reactivity. The genetic and pharmacological manipulation of the TGF-β signaling pathway in animal models of central nervous system (CNS) injury and disease alters pathological and functional outcomes. This review aims to provide recent understanding regarding astrocyte reactivity and TGF-β signaling in brain injury, aging, and neurodegeneration. Further, it explores how TGF-β signaling modulates astrocyte reactivity and function in the context of CNS disease and injury.

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Section: Parkinson's Diseasementioning

confidence: 99%

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Luo

2022

Biomedicines

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“…Hence, to compare our results with experimental data, we searched the literature for any evidence supporting the immune modulatory function of the genes related to microglia. Of the thirteen genes, we found clear evidence in the literature for eight genes on their relevance in microglial function and neuronal inflammation (Mef2a [26], Hdac11 [27,28], Smad3 [29], Mef2c [30], Arid1a [31,32], Zfhx3 [33,34], Ets1 [35], and Jun [36]). Four genes were mentioned in experiments on microglial inflammation (Xrcc5 [37,38], Zfp191 [39], Prdm1 [40], and Usf2 [41]), whereas no information was found in the literature for only two genes (Znf383 and Nfrkb).…”

Section: Immune Cell Activation Modulates Gene Regulatory Network Of ...mentioning

confidence: 72%

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System

Rauthe

Cesnulevicius

Schultz

et al. 2023

IJMS

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Lipid mediators are important regulators in inflammatory responses, and their biosynthetic pathways are targeted by commonly used anti-inflammatory drugs. Switching from pro-inflammatory lipid mediators (PIMs) to specialized pro-resolving (SPMs) is a critical step toward acute inflammation resolution and preventing chronic inflammation. Although the biosynthetic pathways and enzymes for PIMs and SPMs have now been largely identified, the actual transcriptional profiles underlying the immune cell type-specific transcriptional profiles of these mediators are still unknown. Using the Atlas of Inflammation Resolution, we created a large network of gene regulatory interactions linked to the biosynthesis of SPMs and PIMs. By mapping single-cell sequencing data, we identified cell type-specific gene regulatory networks of the lipid mediator biosynthesis. Using machine learning approaches combined with network features, we identified cell clusters of similar transcriptional regulation and demonstrated how specific immune cell activation affects PIM and SPM profiles. We found substantial differences in regulatory networks in related cells, accounting for network-based preprocessing in functional single-cell analyses. Our results not only provide further insight into the gene regulation of lipid mediators in the immune response but also shed light on the contribution of selected cell types in their biosynthesis.

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“…RACK1 is actually suggested modulating VIME by controlling STAT1, STAT3, AP-1, HIF1A, and SMAD3 transcription factors, PKC and AKT kinases as well as the protein phosphatase 2A (PP2A catalytic), and the actin-network component filamin-A. Notably, all these interactors are known to play key roles in NS physiology and their dysfunctions have been associated with several neuropathies, including tauopathies [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

Vantaggiato

Shaba

Carleo

et al. 2022

IJMS

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Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc −/−), heterozygous (galc +/−), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions.

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Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK

Cited by 10 publications

References 79 publications

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System

Neurodegenerative Disorder Risk in Krabbe Disease Carriers

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