Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the ...Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.展开更多
Objective:a-Synuclein has been studied as a potential biomarker for Parkinson's disease(PD)with no concluding results.Accordingly,there is an urgent need to find out reliable specific biomarkers for PD.GPR37 is an...Objective:a-Synuclein has been studied as a potential biomarker for Parkinson's disease(PD)with no concluding results.Accordingly,there is an urgent need to find out reliable specific biomarkers for PD.GPR37 is an orphan G protein-coupled receptor that toxically accumulates in autosomal recessive juvenile parkinsonism.Here,we investigated whether GPR37 is upregulated in sporadic PD,and thus a suitable potential biomarker for PD.Methods:GPR37 protein density and mRNA expression in postmortem substantia nigra(SN)from PD patients were analysed by immunoblot and RT-qPCR,respectively.The presence of peptides from the N-terminus-cleaved domain of GPR37(i.e.ecto-GPR37)in human cerebrospinal fluid(CSF)was determined by liquid chromatography-mass spectrometric analysis.An engineered in-house nanoluciferase-based immunoassay was used to quantify ecto-GPR37 in CSF samples from neurological control(NC)subjects,PD patients and Alzheimer's disease(AD)patients.Results:GPR37 protein density and mRNA expression were significantly augmented in sporadic PD.Increased amounts of ecto-GPR37 peptides in the CSF samples from PD patients were identified by mass spectrometry and quantified by the in-house ELISA method.However,the CSF total a-synuclein level in PD patients did not differ from that in NC subjects.Similarly,the cortical GPR37 mRNA expression and CSF ecto-GPR37 levels in AD patients were also unaltered.Conclusion:GPR37 expression is increased in SN of sporadic PD patients.The ecto-GPR37 peptides are significantly increased in the CSF of PD patients,but not in AD patients.These results open perspectives and encourage further clinical studies to confirm the validity and utility of ecto-GPR37 as a potential PD biomarker.展开更多
Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain sp...Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood-brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer’s and Parkinson’s diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.展开更多
Background: α-Synuclein is a small soluble protein,whose physiological function in the healthy brain is poorly understood.Intracellular inclusions of α-synuclein,referred to as Lewy bodies(LBs),are pathological hall...Background: α-Synuclein is a small soluble protein,whose physiological function in the healthy brain is poorly understood.Intracellular inclusions of α-synuclein,referred to as Lewy bodies(LBs),are pathological hallmarks ofαsynucleinopathies,such as Parkinson’s disease(PD)or dementia with Lewy bodies(DLB).Main body:Understanding of the molecular basis as well as the factors or conditions promoting α-synuclein misfolding and aggregation is an important step towards the comprehension of pathological mechanism ofαsynucleinopathies and for the development of efficient therapeutic strategies.Based on the conversion and aggregation mechanism of α-synuclein,novel diagnostic tests,such as protein misfolding seeded conversion assays,e.g.the real-time quaking-induced conversion(RT-QuIC),had been developed.In diagnostics, α-synuclein RT-QuIC exhibits a specificity between 82 and 100%while the sensitivity varies between 70 and 100%among different laboratories.In addition,the α-synuclein RT-QuIC can be used to study the α-synuclein-seeding-characteristics of different α-synucleinopathies and to differentiate between DLB and PD.Conclusion:The variable diagnostic accuracy of current α-synuclein RT-QuIC occurs due to different protocols,cohorts and material etc..An impact of micro-environmental factors on the α-synuclein aggregation and conversion process and the occurrence and detection of differential misfolded α-synuclein types or strains might underpin the clinical heterogeneity of α-synucleinopathies.展开更多
α-Synucleinopathies,such as Parkinson’s disease(PD),dementia with Lewy bodies(DLB)and multiple system atrophy,are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfoldedα-synuclein(α...α-Synucleinopathies,such as Parkinson’s disease(PD),dementia with Lewy bodies(DLB)and multiple system atrophy,are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfoldedα-synuclein(αSyn),referred to as Lewy bodies or oligodendroglial cytoplasmic inclusions(Papp-Lantos bodies).Even though the specific cellular distribution of aggregatedαSyn differs in PD and DLB patients,both groups show a significant pathological overlap,raising the discussion of whether PD and DLB are the same or different diseases.Besides clinical investigation,we will focus in addition on methodologies,such as protein seeding assays(real-time quaking-induced conversion),to discriminate between different types ofα-synucleinopathies.This approach relies on the seeding conversion properties of misfoldedαSyn,supporting the hypothesis that different conformers of misfoldedαSyn may occur in different types ofα-synucleinopathies.Understanding the pathological processes influencing the disease progression and phenotype,provoked by differentαSyn conformers,will be important for a personalized medical treatment in future.展开更多
基金funded by the Spanish Ministry of Health-Instituto Carlos Ⅲ(Miguel Servet programme-CP/00041) to FL
文摘Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.
基金supported by Ministerio de Ciencia,Innovacion y Universidades-Agencia Estatal de Investigacion/FEDER(SAF2017-87349-R and MDM-2017-0729)ISCIII/FEDER(PIE14/00034 and PI19/00144)+5 种基金Generalitat de Catalunya(2017SGR1604,2017SGR595)Fundacio la Marato de TV3(Grant 20152031)FWO(SBO-140028)ERC consolidator grant(Progsy 649116)Stiftelsen for Strategisk Forskning and a Wallenberg Clinical Scholarship to PS.The CRG/UPF Proteomics Unit is part of the Spanish Infrastruaure for Omics Technologies(ICTS OmicsTech)is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PEI+D+i 2013-2016 from the Instituto de Salud Carlos Ⅲ(ISCⅢ)and ERDF.
文摘Objective:a-Synuclein has been studied as a potential biomarker for Parkinson's disease(PD)with no concluding results.Accordingly,there is an urgent need to find out reliable specific biomarkers for PD.GPR37 is an orphan G protein-coupled receptor that toxically accumulates in autosomal recessive juvenile parkinsonism.Here,we investigated whether GPR37 is upregulated in sporadic PD,and thus a suitable potential biomarker for PD.Methods:GPR37 protein density and mRNA expression in postmortem substantia nigra(SN)from PD patients were analysed by immunoblot and RT-qPCR,respectively.The presence of peptides from the N-terminus-cleaved domain of GPR37(i.e.ecto-GPR37)in human cerebrospinal fluid(CSF)was determined by liquid chromatography-mass spectrometric analysis.An engineered in-house nanoluciferase-based immunoassay was used to quantify ecto-GPR37 in CSF samples from neurological control(NC)subjects,PD patients and Alzheimer's disease(AD)patients.Results:GPR37 protein density and mRNA expression were significantly augmented in sporadic PD.Increased amounts of ecto-GPR37 peptides in the CSF samples from PD patients were identified by mass spectrometry and quantified by the in-house ELISA method.However,the CSF total a-synuclein level in PD patients did not differ from that in NC subjects.Similarly,the cortical GPR37 mRNA expression and CSF ecto-GPR37 levels in AD patients were also unaltered.Conclusion:GPR37 expression is increased in SN of sporadic PD patients.The ecto-GPR37 peptides are significantly increased in the CSF of PD patients,but not in AD patients.These results open perspectives and encourage further clinical studies to confirm the validity and utility of ecto-GPR37 as a potential PD biomarker.
文摘Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood-brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer’s and Parkinson’s diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.
基金The project was supported by the German Academic Exchange Service(DAAD)project 57421248by the Alzheimer Forschung Initiative(AFI)project 17022the Instituto Carlos Ⅲ(Miguel Servet programme—CP16/00041)to FL.
文摘Background: α-Synuclein is a small soluble protein,whose physiological function in the healthy brain is poorly understood.Intracellular inclusions of α-synuclein,referred to as Lewy bodies(LBs),are pathological hallmarks ofαsynucleinopathies,such as Parkinson’s disease(PD)or dementia with Lewy bodies(DLB).Main body:Understanding of the molecular basis as well as the factors or conditions promoting α-synuclein misfolding and aggregation is an important step towards the comprehension of pathological mechanism ofαsynucleinopathies and for the development of efficient therapeutic strategies.Based on the conversion and aggregation mechanism of α-synuclein,novel diagnostic tests,such as protein misfolding seeded conversion assays,e.g.the real-time quaking-induced conversion(RT-QuIC),had been developed.In diagnostics, α-synuclein RT-QuIC exhibits a specificity between 82 and 100%while the sensitivity varies between 70 and 100%among different laboratories.In addition,the α-synuclein RT-QuIC can be used to study the α-synuclein-seeding-characteristics of different α-synucleinopathies and to differentiate between DLB and PD.Conclusion:The variable diagnostic accuracy of current α-synuclein RT-QuIC occurs due to different protocols,cohorts and material etc..An impact of micro-environmental factors on the α-synuclein aggregation and conversion process and the occurrence and detection of differential misfolded α-synuclein types or strains might underpin the clinical heterogeneity of α-synucleinopathies.
基金Open Access funding enabled and organized by Projekt DEAL.This study was funded by the Alzheimer Forschungs Initiative,project number 20026.
文摘α-Synucleinopathies,such as Parkinson’s disease(PD),dementia with Lewy bodies(DLB)and multiple system atrophy,are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfoldedα-synuclein(αSyn),referred to as Lewy bodies or oligodendroglial cytoplasmic inclusions(Papp-Lantos bodies).Even though the specific cellular distribution of aggregatedαSyn differs in PD and DLB patients,both groups show a significant pathological overlap,raising the discussion of whether PD and DLB are the same or different diseases.Besides clinical investigation,we will focus in addition on methodologies,such as protein seeding assays(real-time quaking-induced conversion),to discriminate between different types ofα-synucleinopathies.This approach relies on the seeding conversion properties of misfoldedαSyn,supporting the hypothesis that different conformers of misfoldedαSyn may occur in different types ofα-synucleinopathies.Understanding the pathological processes influencing the disease progression and phenotype,provoked by differentαSyn conformers,will be important for a personalized medical treatment in future.
