Abstract:
:α-synuclein (α-syn) accumulation and aggregation is a common pathological factor found in synucleinopathies, a group of neurodegenerative disorders that includes Parkinson´s disease (PD). It has been proposed that lipid dyshomeostasis is responsible for the occurrence of PD-related processes, however, the precise role of lipids in the onset and progression of neurodegenerative disorders remains unclear. Our aim was to investigate the effect of α-syn overexpression on neutral lipid metabolism and how this impacts on neuronal fate. We found lipid droplet (LD) accumulation in cells overexpressing α-syn to be associated with a rise in triacylglycerol (TAG) and cholesteryl ester (CE) levels. α-syn overexpression promoted diacylglycerol acyltransferase 2 upregulation and acyl-CoA synthetase activation, triggering TAG buildup, that was accompanied by an increase in diacylglycerol acylation. Moreover, the CE increment was associated with higher activity of acyl-CoA:cholesterol acyltransferase. Interestingly, α-syn overexpression increased cholesterol lysosomal accumulation. We observed that sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 were differentially regulated by α-syn overexpression. The latter gave rise to a reduction in SREBP-1 nuclear translocation and consequently in fatty acid synthase expression, whereas it produced an increase in SREBP-2 nuclear localization. Surprisingly, and despite increased cholesterol levels, SREBP-2 downstream genes related to cholesterolgenesis were not upregulated as expected. Notably, phospholipid (PL) levels were diminished in cells overexpressing α-syn. This decrease was related to the activation of phospholipase A2 (PLA2) with a concomitant imbalance of the PL deacylation-acylation cycle. Fatty acids released from PLs by iPLA2 and cPLA2 action were esterified into TAGs, thus promoting a biological response to α-syn overexpression with uncompromised cell viability. When the described steady-state was disturbed under conditions favoring higher levels of α-syn, the response was an enhanced LD accumulation, this imbalance ultimately leading to neuronal death.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Alza NP,Conde MA,Scodelaro-Bilbao PG,Salvador GAdoi
10.1038/s41419-020-03254-7subject
Has Abstractpub_date
2021-01-07 00:00:00pages
52issue
1issn
2041-4889pii
10.1038/s41419-020-03254-7journal_volume
12pub_type
杂志文章abstract::Bevacizumab in neoadjuvant therapy provides a new hope of improved survival for patients with triple-negative breast cancer (TNBC) by targeting vascular endothelial growth factor in combination with chemotherapy, but curative effect is limited by bevacizumab's continuous use while mechanisms remain incompletely unders...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03161-x
更新日期:2020-11-19 00:00:00
abstract::Myotonic dystrophy type 1 (DM1) is the most common type of adult muscular dystrophy caused by the expanded triple-nucleotides (CUG) repeats. Myoblast in DM1 displayed many defects, including defective myoblast differentiation, ribonuclear foci, and aberrant alternative splicing. Despite many were revealed to function ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03112-6
更新日期:2020-10-22 00:00:00
abstract::Circular RNAs (circRNAs), non-coding RNAs generated by precursor mRNA back-splicing of exons, have been reported to fulfill multiple roles in cancer. However, the role of quite a lot circRNAs in colorectal cancer (CRC) remains mostly unknown. Herein, we explored the expression profiles of circRNAs in 5 paired samples ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2514-0
更新日期:2020-05-11 00:00:00
abstract::WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family and functions as a scaffold protein during telomerase assembly, Cajal body formation and DNA double strand break repair. We have previously shown that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung ca...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.162
更新日期:2017-04-13 00:00:00
abstract::DEP-domain containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, has essential roles in several processes, including cell growth, metabolism, apoptosis, and immunity. DEPTOR expression has been shown to be diversely controlled at transcriptional levels in cell- and context-specific manners. However, ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03185-3
更新日期:2020-11-12 00:00:00
abstract::In Slavic folklore, Koschei the Immortal was bony, thin and lean. Was his condition caused by severe calorie restriction (CR)? CR deactivates the target of rapamycin pathway and slows down aging. But the life-extending effect of severe CR is limited by starvation. What if Koschei's anti-aging formula included rapamyci...
journal_title:Cell death & disease
pub_type: 杂志文章,评审
doi:10.1038/cddis.2014.520
更新日期:2014-12-04 00:00:00
abstract::Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen speci...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.492
更新日期:2017-01-19 00:00:00
abstract::Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection that leads to uncontrolled inflammatory response followed by immunosuppression. However, despite the high mortality rate, no specific treatment modality or drugs with high efficacy is available for sepsis to date....
journal_title:Cell death & disease
pub_type: 杂志文章,评审
doi:10.1038/s41419-019-2015-1
更新日期:2019-10-14 00:00:00
abstract::Uncontrollable inflammatory response acts as a driver of sepsis-associated liver injury (SALI). IL-22 plays an important role in regulating inflammatory responses, but its role in SALI remains unknown. The aim of the study was to assess the association of serum IL-22 with SALI in pediatric patients and to enclose the ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03176-4
更新日期:2020-11-11 00:00:00
abstract::Inactivation of the retinoblastoma protein (Rb) has a key role in tumorigenesis. It is well established that Rb function is largely regulated by a dynamic balance of phosphorylation and dephosphorylation. Although much research has been done to understand the mechanisms and function of RB phosphorylation, the regulati...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.3
更新日期:2015-02-12 00:00:00
abstract::Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by dopaminergic neuronal loss that initiates in the substantia nigra pars compacta and by the formation of intracellular inclusions mainly constituted by aberrant α-synuclein (α-syn) deposits known as Lewy bodies. Most cases ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2092-1
更新日期:2019-11-12 00:00:00
abstract::The δ opioid receptor (DOR) is involved in the regulation of malignant transformation and tumor progression of hepatocellular carcinoma (HCC). However, regulation of the DOR in HCC remains poorly defined. We found that miR-874 was identified as a negative regulator of the DOR, which is a direct and functional target o...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-017-0131-3
更新日期:2018-01-26 00:00:00
abstract::One of the significant challenges for chemotherapy is the appearance of resistance to compounds. Although several signaling pathways have been implicated in the development of Adriamycin (ADM) resistance, mechanisms involved in ADM-resistant osteosarcoma progression remain unknown. The present study attempted to illus...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2573-2
更新日期:2020-05-13 00:00:00
abstract::Polo-like kinase 1 (PLK1) is an important mitotic kinase and its expression is tightly regulated in the cell cycle and in the DNA damage response. PLK1 expression is previously shown to be suppressed by p53 and/or p21. Here, we demonstrate that the CCAAT box in the PLK1 promoter is pivotal for p53/p21-mediated PLK1 re...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.527
更新日期:2014-01-09 00:00:00
abstract::Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer (CRC) patients. The role of the differentially expressed lncRNAs in 5-Fluorouracil chemoresistance has not fully explained. Here, we observed lncRNA H19 was associated with the 5-Fu resistance in CRC. Quantitative analysis in...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1187-4
更新日期:2018-11-19 00:00:00
abstract::The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress is a feature of many neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease (PD). Although the vast majority of PD is sporadic, mutations in a number of genes including PARK7 which encodes...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1354-2
更新日期:2019-02-12 00:00:00
abstract::The vascular leakage in diabetic retinopathy leads to macular edema and vision loss. Although astrocyte play an important role in regulating blood-brain barrier integrity in the brain, the precise role of astrocyte in blood-retinal barrier was yet to be elucidated. This study aimed to investigate the role of angiopoie...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.347
更新日期:2016-02-18 00:00:00
abstract::Highly conserved microRNA-9 (miR-9) has a critical role in various cellular processes including neurogenesis. However, its regulation by neurotropins that are known to mediate neurogenesis remains poorly defined. In this study, we identify platelet-derived growth factor-BB (PDGF-BB)-mediated upregulation of miR-9, whi...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.486
更新日期:2013-12-12 00:00:00
abstract::An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title:Cell death & disease
pub_type: 已发布勘误
doi:10.1038/s41419-019-1722-y
更新日期:2019-06-17 00:00:00
abstract::Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viab...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.144
更新日期:2016-05-26 00:00:00
abstract::miR-195 has recently been reported to function as a tumor suppressor in various cancers, including non-small cell lung cancer (NSCLC). However, the mechanisms by which miR-195 represses the tumorigenesis of NSCLC cells are not fully understood. We performed a high-throughput screen using an miRNA mimic library and con...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-017-0219-9
更新日期:2018-02-07 00:00:00
abstract::Enhanced Myd88 expression has been found in various parenchymal tumors especially in hepatocellular carcinoma with little mechanism of its upregulation known. A lot of long non-coding RNAs are reported to regulate the protein-coding genes which have location association through various mechanisms. In our study we conf...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.519
更新日期:2017-10-12 00:00:00
abstract::Human glioma-associated mesenchymal stem cells (gbMSCs) are the stromal cell components that contribute to the tumourigenesis of malignant gliomas. Recent studies have shown that gbMSCs consist of two distinct subpopulations (CD90+ and CD90- gbMSCs). However, the different roles in glioma progression have not been exp...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1140-6
更新日期:2018-10-27 00:00:00
abstract::Mitochondrial membrane potential provides a valuable indicator of cells' health and functional status. Cytometry- and microscopy-based analyses, in combination with fluorescent probes, are widely used to study mitochondrial behavior related to cellular pathways, most notably - apoptosis. The cyanine dye JC-1 (5,5',6,6...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2012.171
更新日期:2012-11-22 00:00:00
abstract::Homeostatic chemokines, such as CXCL12, can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission, but the mechanisms involved are still undefined. Our previous studies have shown that CXCL12 protects cortical neurons from excitotoxicity by promoting the function of the gene-repress...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2010.10
更新日期:2010-04-01 00:00:00
abstract::Proinflammatory cytokines exert cytotoxic effects on β-cells, and are involved in the pathogenesis of type I and type II diabetes and in the drastic loss of β-cells following islet transplantation. Cytokines induce apoptosis and alter the function of differentiated β-cells. Although the MAP3 kinase tumor progression l...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.399
更新日期:2016-01-21 00:00:00
abstract::We sought to identify miRNAs that can efficiently induce apoptosis in ovarian cancer cells by overcoming BCL-X(L) and MCL1 anti-apoptotic activity, using combined computational and experimental approaches. We found that miR-491-5p efficiently induces apoptosis in IGROV1-R10 cells by directly inhibiting BCL-X(L) expres...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.389
更新日期:2014-10-09 00:00:00
abstract::Pin1 is the only known peptidyl-prolyl cis-trans isomerase (PPIase) that specifically recognizes and isomerizes the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif. The Pin1-mediated structural transformation posttranslationally regulates the biofunctions of multiple proteins. Pin1 is involved in many cel...
journal_title:Cell death & disease
pub_type: 杂志文章,评审
doi:10.1038/s41419-018-0844-y
更新日期:2018-08-29 00:00:00
abstract::Chronic lymphocytic leukemia (CLL) can be divided into groups based on biomarkers of poor prognosis. The expression of the tyrosine kinase ZAP-70 (member of the Syk tyrosine kinase family) in CLL cells is associated with shorter overall survival in CLL patients. Currently, there is a lack of targeted therapies for pat...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.391
更新日期:2014-10-02 00:00:00
abstract::The original version of this article contained an error in the name of one of the co-authors (Kayvan Mohkam). This has been corrected in the PDF and HTML versions. ...
journal_title:Cell death & disease
pub_type: 已发布勘误
doi:10.1038/s41419-020-2262-1
更新日期:2020-01-23 00:00:00