摘要
Neurodegenerative disorders are often associated with cellular dysfunction caused by underlying protein-misfolding signalling. Numerous neuropathologies are diagnosed at late stage symptomatic changes which occur in response to these molecular malfunctions and treatment is often too late or restricted only to the slowing of further cell death. Important new strategies to identify early biomarkers with predictive value to intervene with disease progression at stages where cell dysfunction has not progressed irreversibly is of paramount importance. Thus, the identification of these markers presents an essential opportunity to identify and target disease pathways. This review highlights some important metabolic alterations detected in neurodegeneration caused by misfolded prion protein and discusses common toxicity pathways identified across different neurodegenerative diseases. Thus, having established some commonalities between various degenerative conditions, detectable metabolic changes may be of extreme value as an early diagnostic biomarker in disease.
Neurodegenerative disorders are often associated with cellular dysfunction caused by underlying protein-misfolding signalling. Numerous neuropathologies are diagnosed at late stage symptomatic changes which occur in response to these molecular malfunctions and treatment is often too late or restricted only to the slowing of further cell death. Important new strategies to identify early biomarkers with predictive value to intervene with disease progression at stages where cell dysfunction has not progressed irreversibly is of paramount importance. Thus, the identification of these markers presents an essential opportunity to identify and target disease pathways. This review highlights some important metabolic alterations detected in neurodegeneration caused by misfolded prion protein and discusses common toxicity pathways identified across different neurodegenerative diseases. Thus, having established some commonalities between various degenerative conditions, detectable metabolic changes may be of extreme value as an early diagnostic biomarker in disease.
引文
Aguzzi A,Calella AM(2009)Prions:protein aggregation and infectious diseases.Physiol Rev 89:1105-1152.
An Y,Varma VR,Varma S,Casanova R,Dammer E,Pletnikova O,Chia CW,Egan JM,Ferrucci L,Troncoso J,Levey AI,Lah J,Seyfried NT,Legido-Quigley C,O’Brien R,Thambisetty M(2018)Evidence for brain glucose dysregulation in Alzheimer’s disease.Alzheimers Dement 14:318-329.
Bamji-Stocke S,van Berkel V,Miller DM,Frieboes HB(2018)A review of metabolism-associated biomarkers in lung cancer diagnosis and treatment.Metabolomics 14:81.
Bode-Boger SM,Scalera F,Ignarro LJ(2007)The L-arginine paradox:Importance of the L-arginine/asymmetrical dimethylarginine ratio.Pharmacol Ther 114:295-306.
Bourgognon JM,Spiers JG,Bradley SJ,Scheiblich H,Antonov A,Tobin AB,Steinert JR(2018)Alterations in neuronal metabolism contribute to the pathogenesis of prion disease.Cell Death Differ 25:1408-1425
Bradley SA,Steinert JR(2016)Nitric oxide-mediated posttranslational modifications:impacts at the synapse.Oxid Med Cell Longev2016:5681036.
Calabrese V,Cornelius C,Rizzarelli E,Owen JB,Dinkova-Kostova AT,Butterfield DA(2009)Nitric oxide in cell survival:a janus molecule.Antioxid Redox Signal 11:2717-2739.
Dong MX,Feng X,Xu XM,Hu L,Liu Y,Jia SY,Li B,Chen W,Wei YD(2018)Integrated analysis reveals altered lipid and glucose metabolism and identifies NOTCH2 as a biomarker for Parkinson’s disease related depression.Front Mol Neurosci 11:257.
Garthwaite J(2016)From synaptically localized to volume transmission by nitric oxide.J Physiol 594:9-18.
Ibanez C,Cifuentes A,Simo C(2015)Recent advances and applications of metabolomics to investigate neurodegenerative diseases.Int Rev Neurobiol 122:95-132.
Laurens B,Constantinescu R,Freeman R,Gerhard A,Jellinger K,Jeromin A,Krismer F,Mollenhauer B,Schlossmacher MG,Shaw LM,Verbeek MM,Wenning GK,Winge K,Zhang J,Meissner WG(2015)Fluid biomarkers in multiple system atrophy:a review of the MSABiomarker Initiative.Neurobiol Dis 80:29-41.
Lewitt PA,Li J,Lu M,Beach TG,Adler CH,Guo L,Arizona Parkinson’s Disease C(2013)3-Hydroxykynurenine and other Parkinson’s disease biomarkers discovered by metabolomic analysis.Mov Disord28:1653-1660.
Lourenco CF,Ledo A,Barbosa RM,Laranjinha J(2017)Neurovascular-neuroenergetic coupling axis in the brain:master regulation by nitric oxide and consequences in aging and neurodegeneration.Free Radic Biol Med 108:668-682.
Nakamura T,Lipton SA(2016)Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases.Trends Pharmacol Sci 37:73-84.
Nakamura T,Lipton SA(2017)‘SNO’-storms compromise protein activity and mitochondrial metabolism in neurodegenerative disorders.Trends Endocrinol Metab 28:879-892.
Nakamura T,Tu S,Akhtar MW,Sunico CR,Okamoto S,Lipton SA(2013)Aberrant protein S-nitrosylation in neurodegenerative diseases.Neuron 78:596-614.
Sonntag KC,Ryu WI,Amirault KM,Healy RA,Siegel AJ,McPhie DL,Forester B,Cohen BM(2017)Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles.Sci Rep7:14038.
Steinert JR,Chernova T,Forsythe ID(2010)Nitric oxide signaling in brain function,dysfunction,and dementia.Neuroscientist 16:435-452.
Taha TA,Mullen TD,Obeid LM(2006)A house divided:ceramide,sphingosine,and sphingosine-1-phosphate in programmed cell death.Biochim Biophys Acta 1758:2027-2036.
Tesfai A,MacCallum N,Kirkby NS,Gashaw H,Gray N,Want E,Quinlan GJ,Mumby S,Leiper JM,Paul-Clark M,Ahmetaj-Shala B,Mitchell JA(2017)Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways.PLoS One 12:e0183025.
Wang R,Li Y,Tsung A,Huang H,Du Q,Yang M,Deng M,Xiong S,Wang X,Zhang L,Geller DA,Cheng B,Billiar TR(2018)iNOS promotes CD24(+)CD133(+)liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway.Proc Natl Acad Sci U S A 115:E10127-10136.
Yu M,Sun S,Yu J,Du F,Zhang S,Yang W,Xiao J,Xie B(2018)Discovery and validation of potential serum biomarkers for pediatric patients with congenital heart diseases by metabolomics.J Proteome Res 17:3517-3525.
