Endoplasmic Reticulum Malfunction in the Nervous System

Jung, Joanna; Michalak, Marek; Agellon, Luis B.

doi:10.3389/fnins.2017.00220

Cited by 22 publications

(19 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that a deficiency in Fabp5 also protects against EAE (39,40). It is tempting to speculate that the calnexin/Fabp5 complex is a component of neuroproteostasis and lipidostasis (41). The dysregulation of calnexin/Fabp5 function may be a key event in the pathogenesis of MS and represents an important target for therapeutics development aimed at promoting favorable clinical outcomes for patients afflicted with MS.…”

Section: Discussionmentioning

confidence: 99%

Calnexin is necessary for T cell transmigration into the central nervous system

Jung¹,

Eggleton²,

Robinson³

et al. 2018

JCI Insight

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Calnexin is necessary for T cell transmigration into the central nervous system

Jung¹,

Eggleton²,

Robinson³

et al. 2018

JCI Insight

Self Cite

View full text Add to dashboard Cite

“…Dysregulated cellular stress coping responses, including UPR and genome damage response, are drivers of multiple pathological conditions, ranging from cancer, neurodegeneration, inflammatory, and metabolic disorders 4 , 46 – 48 . In the case of ER stress, IRE1α initiates the most conserved signaling branch of the UPR which affects many cellular processes including cellular energetics 49 , 50 , inflammation 51 , immunity 52 , angiogenesis 53 , aging and longevity 54 , and neurodegeneration 4 , 31 , 55 – 58 . However, the molecular mechanism(s) responsible for cyclosporine-dependent activation of the UPR have long remained poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine A binding to COX-2 reveals a novel signaling pathway that activates the IRE1α unfolded protein response sensor

Groenendyk

Paškevičius

Urra

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

Cyclosporine, a widely used immunosuppressant in organ transplantation and in treatment of various autoimmune diseases, activates the unfolded protein response (UPR), an ER stress coping response. In this study we discovered a new and unanticipated cyclosporine-dependent signaling pathway, with cyclosporine triggering direct activation of the UPR. COX-2 binds to and activates IRE1α, leading to IRE1α splicing of XBP1 mRNA. Molecular interaction and modeling analyses identified a novel interaction site for cyclosporine with COX-2 which caused enhancement of COX-2 enzymatic activity required for activation of the IRE1α branch of the UPR. Cyclosporine-dependent activation of COX-2 and IRE1α in mice indicated that cyclosporine-COX-2-IRE1α signaling pathway was functional in vivo. These findings identify COX-2 as a new IRE1α binding partner and regulator of the IRE1α branch of the UPR pathway, and establishes the mechanism underlying cytotoxicity associated with chronic cyclosporine exposure.

show abstract

“…All the enzymes involved in the de novo synthesis of sphingolipids normally reside in the ER (Breslow, 2013 ; Siow et al, 2015 ), which has long been strongly implicated in the pathology of HD (Jiang et al, 2016 ; Jung et al, 2017 ). Whether the dysfunctional sphingolipid synthesis reported in this study is a causing factor or a consequence of the ER abnormalities in HD cannot be clarified here.…”

Section: Discussionmentioning

confidence: 99%

De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease

et al. 2017

View full text Add to dashboard Cite

Alterations of lipid metabolism have been frequently associated with Huntington's disease (HD) over the past years. HD is the most common neurodegenerative disorder, with a complex pathogenic profile, typically characterized by progressive striatal and cortical degeneration and associated motor, cognitive and behavioral disturbances. Previous findings from our group support the idea that disturbed sphingolipid metabolism could represent an additional hallmark of the disease. Although such a defect represents a common biological denominator among multiple disease models ranging from cells to humans through mouse models, more efforts are needed to clearly define its clinical significance and the role it may play in the progression of the disease. In this study, we provided the first evidence of a defective de novo biosynthetic pathway of sphingolipids in multiple HD pre-clinical models. qPCR analysis revealed perturbed gene expression of sphingolipid-metabolizing enzymes in both early and late stage of the disease. In particular, reduction in the levels of sptlc1 and cerS1 mRNA in the brain tissues from manifest HD mice resulted in a significant decrease in the content of dihydroSphingosine, dihydroSphingosine-1-phospahte and dihydroCeramide [C18:0] as assessed by mass spectrometry. Moreover, in vitro studies highlighted the relevant role that aberrant sphingolipid metabolism may have in the HD cellular homeostasis. With this study, we consolidate the evidence of disturbed sphingolipid metabolism in HD and demonstrate for the first time that the de novo biosynthesis pathway is also significantly affected in the disease. This finding further supports the hypothesis that perturbed sphingolipid metabolism may represent a crucial factor accounting for the high susceptibility to disease in HD.

show abstract

Endoplasmic Reticulum Malfunction in the Nervous System

Cited by 22 publications

References 99 publications

Calnexin is necessary for T cell transmigration into the central nervous system

Calnexin is necessary for T cell transmigration into the central nervous system

Cyclosporine A binding to COX-2 reveals a novel signaling pathway that activates the IRE1α unfolded protein response sensor

De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease

Contact Info

Product

Resources

About