1,721,133 research outputs found
Regulation of human cerebrospinal fluid malate dehydrogenase 1 in sporadic Creutzfeldt-Jakob disease patients
No full textThe identification of reliable diagnostic biomarkers in differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous two-dimensional proteomic study on cerebrospinal fluid (CSF) revealed an elevated level of an enzyme, mitochondria! malate dehydrogenase 1 (MDH1), in sporadic Creutzfeldt-Jakob disease (sCJD) patients. Here, we could demonstrate the expression of MDH1 in neurons as well as in the neuropil. Its levels are lower in sCJD brains than in control brains. An examination of CSF-MDH1 in sCJD patients by ELISA revealed a significant elevation of CSF-MDH1 levels in sCJD patients (independently from the PRNP codon 129 MV genotype or the prion protein scrapie (PrPsc) type) in comparison to controls. In combination with total tau (tau), CSF-MDH1 detection exhibited a high diagnostic accuracy for sCJD diagnosis with a sensitivity of 97.5% and a specificity of 95.6%. A correlation study of MDH1 level in CSF with other neurodegenerative marker proteins revealed a significant positive correlation between MDH1 concentration with tau, 14-3-3 and neuron specific enolase level. In conclusion, our study indicated the potential of MDH1 in combination with tau as an additional biomarker in sCJD improving diagnostic accuracy of tau markedly.Open-Access-Publikationsfonds 201
MicroRNA Alterations in the Brain and Body Fluids of Humans and Animal Prion Disease Models: Current Status and Perspectives
No full textPrion diseases are transmissible progressive neurodegenerative conditions characterized by rapid neuronal loss accompanied by a heterogeneous neuropathology, including spongiform degeneration, gliosis and protein aggregation. The pathogenic mechanisms and the origins of prion diseases remain unclear on the molecular level. Even though neurodegenerative diseases, including prion diseases, represent distinct entities, their pathogenesis shares a number of features including disturbed protein homeostasis, an overload of protein clearance pathways, the aggregation of pathological altered proteins, and the dysfunction and/or loss of specific neuronal populations. Recently, direct links have been established between neurodegenerative diseases and miRNA dysregulated patterns. miRNAs are a class of small non-coding RNAs involved in the fundamental post-transcriptional regulation of gene expression. Studies of miRNA alterations in the brain and body fluids in human prion diseases provide important insights into potential miRNA-associated disease mechanisms and biomarker candidates. miRNA alterations in prion disease models represent a unique tool to investigate the cause-consequence relationships of miRNA dysregulation in prion disease pathology, and to evaluate the use of miRNAs in diagnosis as biomarkers. Here, we provide an overview of studies on miRNA alterations in human prion diseases and relevant disease models, in relation to pertinent studies on other neurodegenerative diseases
Comparative interactome mapping of Tau‐protein in classical and rapidly progressive Alzheimer's disease identifies subtype‐specific pathways
No full textAbstract
Aims
Tau is a key player in Alzheimer's disease (AD) and other Tauopathies. Tau pathology in the brain directly correlates with neurodegeneration in AD. The recent identification of a rapid variant of AD demands an urgent need to uncover underlying mechanisms leading to differential progression in AD. Accordingly, we aimed to dissect the underlying differential mechanisms of toxicity associated with the Tau protein in AD subtypes and to find out subtype‐dependent biomarkers and therapeutic targets.
Methods
To identify and characterise subtype‐specific Tau‐associated mechanisms of pathology, we performed comparative interactome mapping of Tau protein in classical AD (cAD) and rapidly progressive AD (rpAD) cases using co‐immunoprecipitation coupled with quantitative mass spectrometry. The mass spectrometry data were extensively analysed using several bioinformatics approaches.
Results
The comparative interactome mapping of Tau protein revealed distinct and unique interactors (DPYSL4, ARHGEF2, TUBA4A and UQCRC2) in subtypes of AD. Interestingly, an analysis of the Tau‐interacting proteins indicated enrichment of mitochondrial organisation processes, including negative regulation of mitochondrion organisation, mitochondrial outer membrane permeabilisation involved in programmed cell death, regulation of autophagy of mitochondrion and necroptotic processes, specifically in the rpAD interactome. While, in cAD, the top enriched processes were related to oxidation–reduction process, transport and monocarboxylic acid metabolism.
Conclusions
Overall, our results provide a comprehensive map of Tau‐interacting protein networks in a subtype‐dependent manner and shed light on differential functions/pathways in AD subtypes. This comprehensive map of the Tau‐interactome has provided subsets of disease‐related proteins that can serve as novel biomarkers/biomarker panels and new drug targets
Prion protein interactome: Identifying novel targets in rapidly progressive Alzheimer's disease
No full text
Prion protein interactome: Identifying novel targets in rapidly progressive Alzheimer's disease
No full textProteomic Profiling Reveals Mitochondrial Dysregulation in Rapidly Progressive Alzheimer’s: Role of DLDH in Amyloid Beta Aggregation
No full textAbstract Alzheimer’s disease (AD) is presented as multiple clinical variants depending upon the rate of progression and familial background; however, the exact molecular mechanisms associated with these subtypes and their treatments are yet to be understood. The current study is based on a global proteome analysis of brain samples from patients ( n = 38) with rapidly progressive AD (rpAD—survival time < 3 years), sporadic AD (spAD—survival time of 8–10 years), and healthy controls. Proteome analysis revealed a differential regulation of 79 proteins and highlighted the dysregulation of mitochondrial machinery and glucose metabolism in rpAD. Dihydrolipoamide dehydrogenase (DLDH), a mitochondrial oxidoreductase, showed a significant reduction and delocalization in rpAD. In vitro analysis revealed a potential role of DLDH in the aggregation of amyloid beta. Rapid progression in AD may be influenced by the energy homeostasis and redox dysfunction linked with the DLDH.NRPU; Higher Education Commission of PakistanInternational Brain Research Organization https://doi.org/10.13039/501100001675EU Joint Programme – Neurodegenerative Disease Research http://dx.doi.org/10.13039/100013278Herzzentrum Göttinge
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