Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkin...Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.展开更多
Background Adipose tissue plays a central role in regulating whole-body metabolic health,facilitated by the variety of cell types and their wide-ranging functions.In addition,depot-specific differences in adipose tiss...Background Adipose tissue plays a central role in regulating whole-body metabolic health,facilitated by the variety of cell types and their wide-ranging functions.In addition,depot-specific differences in adipose tissue have been shown to play important roles in different disease states including obesity,diabetes,and metabolic dysfunction in human and animal models.For early postpartum dairy cattle,metabolic dysfunction,triggered by a negative energy balance,is often manifested as subclinical ketosis(SCK).However,the role that subcutaneous(SAT)and visceral(VAT)adipose tissue depots,and their diverse cellular compositions,play in the response to subclinical ketosis conditions is unclear.Results Flank SAT and omental VAT were collected via laparotomy from five non-ketotic(NK;BHB≤0.8 mmol/L)and five subclinical ketosis(SCK;1.4 mmol/L<BHB≤2.6 mmol/L)multiparous cows during early lactation.Following collection,nuclei were isolated from the tissue and subjected to single-nuclei RNA sequencing in order to investigate the transcriptional cellular heterogeneity.Distinct clusters of adipocytes(AD),adipose stem/progenitor cells(ASPC),immune cells(IMC),endothelial cells(EC),and pericyte/smooth muscle cells(PE/SMC)were identified in both adipose depots,with a greater abundance of ASPC in SAT compared to VAT.In addition,we identified a VAT-specific AD subtype characterized by higher expression of progenitor-like marker genes.While the abundance of none of the identified cell subtypes were different between SCK and NK,underlying transcriptional changes provided insight into potential effects of SCK.In general,SCK was associated with pro-lipogenic,anti-inflammatory,and pro-angiogenic transcriptional changes,possibly indicating a greater capacity for homeostatic responsiveness in SAT under conditions of enhanced negative energy balance.In contrast,SCK appeared to promote transcriptional changes indicative of impaired adipogenesis,impaired angiogenesis,and increased inflammation in VAT.Conclusions Uniquely,our study presents novel insight into the cellular heterogeneity of adipose tissue in dairy cattle with subclinical ketosis.Furthering our understanding of the role of adipose tissue in response to this form of metabolic challenge has the potential to enhance efforts aimed at limiting the incidence and impact of subclinical ketosis and improving the health and productivity of dairy cattle.展开更多
基金supported by the National Natural Science Foundation of China,No. 81971006 (to DSG)。
文摘Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.
基金supported in part by the Agriculture and Food Research Initiative Competitive Grants#2022-67015-36319 and#2024-67034-42234 from USDA-NIFA(United States Department of Agriculture–National Institute of Food and Agriculture).
文摘Background Adipose tissue plays a central role in regulating whole-body metabolic health,facilitated by the variety of cell types and their wide-ranging functions.In addition,depot-specific differences in adipose tissue have been shown to play important roles in different disease states including obesity,diabetes,and metabolic dysfunction in human and animal models.For early postpartum dairy cattle,metabolic dysfunction,triggered by a negative energy balance,is often manifested as subclinical ketosis(SCK).However,the role that subcutaneous(SAT)and visceral(VAT)adipose tissue depots,and their diverse cellular compositions,play in the response to subclinical ketosis conditions is unclear.Results Flank SAT and omental VAT were collected via laparotomy from five non-ketotic(NK;BHB≤0.8 mmol/L)and five subclinical ketosis(SCK;1.4 mmol/L<BHB≤2.6 mmol/L)multiparous cows during early lactation.Following collection,nuclei were isolated from the tissue and subjected to single-nuclei RNA sequencing in order to investigate the transcriptional cellular heterogeneity.Distinct clusters of adipocytes(AD),adipose stem/progenitor cells(ASPC),immune cells(IMC),endothelial cells(EC),and pericyte/smooth muscle cells(PE/SMC)were identified in both adipose depots,with a greater abundance of ASPC in SAT compared to VAT.In addition,we identified a VAT-specific AD subtype characterized by higher expression of progenitor-like marker genes.While the abundance of none of the identified cell subtypes were different between SCK and NK,underlying transcriptional changes provided insight into potential effects of SCK.In general,SCK was associated with pro-lipogenic,anti-inflammatory,and pro-angiogenic transcriptional changes,possibly indicating a greater capacity for homeostatic responsiveness in SAT under conditions of enhanced negative energy balance.In contrast,SCK appeared to promote transcriptional changes indicative of impaired adipogenesis,impaired angiogenesis,and increased inflammation in VAT.Conclusions Uniquely,our study presents novel insight into the cellular heterogeneity of adipose tissue in dairy cattle with subclinical ketosis.Furthering our understanding of the role of adipose tissue in response to this form of metabolic challenge has the potential to enhance efforts aimed at limiting the incidence and impact of subclinical ketosis and improving the health and productivity of dairy cattle.
