The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.
DengYTYouJHeY, et al.Atlas of the plasma proteome in health and disease in 53,026 adults. Cell2025; 188: 253–271.e257.
2.
NestlerEJGreengardP. Protein phosphorylation in the brain. Nature1983; 305: 583–588.
3.
KellarDCraftS. Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol2020; 19: 758–766.
4.
Fernandez-IrigoyenJCorralesFSantamariaE. The Human Brain Proteome Project: biological and technological challenges. Methods Mol Biol2019; 2044: 3–23.
5.
ZahidSOellerichMAsifAR, et al.Phosphoproteome profiling of substantia nigra and cortex regions of Alzheimer's disease patients. J Neurochem2012; 121: 954–963.
6.
DammerEBLeeAKDuongDM, et al.Quantitative phosphoproteomics of Alzheimer's disease reveals cross-talk between kinases and small heat shock proteins. Proteomics2015; 15: 508–519.
7.
TriplettJCSwomleyAMCaiJ, et al.Quantitative phosphoproteomic analyses of the inferior parietal lobule from three different pathological stages of Alzheimer's disease. J Alzheimers Dis2015; 49: 45–62.
8.
PingLKundingerSRDuongDM, et al.Global quantitative analysis of the human brain proteome and phosphoproteome in Alzheimer's disease. Sci Data2020; 7: 15.
9.
FerrerIAndres-BenitoPAusinK, et al.Dysregulated protein phosphorylation: a determining condition in the continuum of brain aging and Alzheimer's disease. Brain Pathol2021; 31: e12996.
10.
BaiBWangXLiY, et al.Deep multilayer brain proteomics identifies molecular networks in Alzheimer's disease progression. Neuron2020; 105: 975–991 e977.
11.
MorshedNLeeMJRodriguezFH, et al.Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer's disease. Nat Aging2021; 1: 550–565.
12.
WangFBlanchardAPElismaF, et al.Phosphoproteome analysis of an early onset mouse model (TgCRND8) of Alzheimer's disease reveals temporal changes in neuronal and glia signaling pathways. Proteomics2013; 13: 1292–1305.
13.
HoosMDRichardsonBMFosterMW, et al.Longitudinal study of differential protein expression in an Alzheimer's mouse model lacking inducible nitric oxide synthase. J Proteome Res2013; 12: 4462–4477.
14.
TagawaKHommaHSaitoA, et al.Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain. Hum Mol Genet2015; 24: 540–558.
15.
WangQXiaCZhuA, et al.Discrepancy of synaptic and microtubular protein phosphorylation in the hippocampus of APP/PS1 and MAPTxP301S transgenic mice at the early stage of Alzheimer's disease. Metab Brain Dis2023; 38: 1983–1997.
16.
MeesITranHRobertsA, et al.Quantitative phosphoproteomics reveals extensive protein phosphorylation dysregulation in the cerebral cortex of Huntington's disease mice prior to onset of symptoms. Mol Neurobiol2022; 59: 2456–2471.
17.
MeesILiSTranH, et al.Phosphoproteomic dysregulation in Huntington's disease mice is rescued by environmental enrichment. Brain Commun2022; 4: fcac305.
18.
GarridoASantamariaEFernandez-IrigoyenJ, et al.Differential phospho-signatures in blood cells identify LRRK2 G2019S carriers in Parkinson's disease. Mov Disord2022; 37: 1004–1015.
19.
LaiYCKondapalliCLehneckR, et al.Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1. EMBO J2015; 34: 2840–2861.
20.
StegerMTonelliFItoG, et al.Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of rab GTPases. Elife2016; 5: e12813.
21.
BogetofteHRyanBJJensenP, et al.Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons. Cell Rep2023; 42: 112180.
22.
WanHTangBLiaoX, et al.Analysis of neuronal phosphoproteome reveals PINK1 regulation of BAD function and cell death. Cell Death Differ2018; 25: 904–917.
23.
FujiwaraHHasegawaMDohmaeN, et al.alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol2002; 4: 160–164.
24.
TolosaEVilaMKleinC, et al.LRRK2 In Parkinson disease: challenges of clinical trials. Nat Rev Neurol2020; 16: 97–107.
25.
AsanoTNakamuraHKawamotoY, et al.Inhibition of Crmp1 phosphorylation at Ser522 ameliorates motor function and neuronal pathology in amyotrophic lateral sclerosis model mice. eNeuro2022; 9: ENEURO.0133-22.2022.
26.
JiangWZhangPYangP, et al.Phosphoproteome analysis identifies a synaptotagmin-1-associated complex involved in ischemic neuron injury. Mol Cell Proteomics2022; 21: 100222.
27.
SongHChenMChenC, et al.Proteomic analysis and biochemical correlates of mitochondrial dysfunction after low-intensity primary blast exposure. J Neurotrauma2019; 36: 1591–1605.
28.
MorinADavisRDarceyT, et al.Subacute and chronic proteomic and phosphoproteomic analyses of a mouse model of traumatic brain injury at two timepoints and comparison with chronic traumatic encephalopathy in human samples. Mol Brain2022; 15: 62.
29.
DrastichovaZHejnovaLMoravcovaR, et al.Proteomic analysis unveils expressional changes in cytoskeleton- and synaptic plasticity-associated proteins in rat brain six months after withdrawal from morphine. Life (Basel)2021; 11: 683.
30.
UjcikovaHEckhardtAHejnovaL, et al.Alterations in the proteome and phosphoproteome profiles of rat hippocampus after six months of morphine withdrawal: comparison with the forebrain cortex. Biomedicines2021; 10: 80.
31.
LiawWJTsaoCMHuangGS, et al.Phosphoproteomics and bioinformatics analyses of spinal cord proteins in rats with morphine tolerance. PLoS One2014; 9: e83817.
32.
RichMTAbbottTBChungL, et al.Phosphoproteomic analysis reveals a novel mechanism of CaMKIIalpha regulation inversely induced by cocaine memory extinction versus reconsolidation. J Neurosci2016; 36: 7613–7627.
33.
KondoAShahpasandKMannixR, et al.Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature2015; 523: 431–436.
34.
Vicente-RodriguezMGramageEHerradonG, et al.Phosphoproteomic analysis of the striatum from pleiotrophin knockout and midkine knockout mice treated with cocaine reveals regulation of oxidative stress-related proteins potentially underlying cocaine-induced neurotoxicity and neurodegeneration. Toxicology2013; 314: 166–173.
35.
LiuJJSharmaKZangrandiL, et al.In vivo brain GPCR signaling elucidated by phosphoproteomics. Science2018; 360: eaao4927.
36.
LiuJJChiuYTDiMattioKM, et al.Phosphoproteomic approach for agonist-specific signaling in mouse brains: mTOR pathway is involved in kappa opioid aversion. Neuropsychopharmacology2019; 44: 939–949.
37.
Martins-de-SouzaDGuestPCVanattou-SaifoudineN, et al.Phosphoproteomic differences in major depressive disorder postmortem brains indicate effects on synaptic function. Eur Arch Psychiatry Clin Neurosci2012; 262: 657–666.
38.
LiQCaiDHuangH, et al.Phosphoproteomic profiling of the hippocampus of offspring rats exposed to prenatal stress. Brain Behav2021; 11: e2233.
39.
ReddyJSJinJLincolnSJ, et al.Transcript levels in plasma contribute substantial predictive value as potential Alzheimer's disease biomarkers in African Americans. EBioMedicine2022; 78: 103929.
40.
FanYHowdenAJMSarhanAR, et al.Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils. Biochem J2018; 475: 23–44.
41.
AtashrazmFHammondDPereraG, et al.LRRK2-mediated Rab10 phosphorylation in immune cells from Parkinson's disease patients. Mov Disord2019; 34: 406–415.
42.
CariuloCAzzolliniLVeraniM, et al.Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation. Proc Natl Acad Sci U S A2017; 114: E10809–E10818.
43.
GrossmanMElmanLMcCluskeyL, et al.Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. JAMA Neurol2014; 71: 442–448.
44.
CousinsKAQShawLMShellikeriS, et al.Elevated plasma phosphorylated tau 181 in amyotrophic lateral sclerosis. Ann Neurol2022; 92: 807–818.
45.
RivaNGentileFCerriF, et al.Phosphorylated TDP-43 aggregates in peripheral motor nerves of patients with amyotrophic lateral sclerosis. Brain2022; 145: 276–284.
46.
PetratosSOzturkEAzariMF, et al.Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP-2 phosphorylation. Brain2012; 135: 1794–1818.
47.
PetzoldAGvericDGrovesM, et al.Phosphorylation and compactness of neurofilaments in multiple sclerosis: indicators of axonal pathology. Exp Neurol2008; 213: 326–335.
48.
SinghPYanJHullR, et al.Levels of phosphorylated axonal neurofilament subunit H (pNfH) are increased in acute ischemic stroke. J Neurol Sci2011; 304: 117–121.
49.
Pujol-CalderonFPorteliusEZetterbergH, et al.Neurofilament changes in serum and cerebrospinal fluid after acute ischemic stroke. Neurosci Lett2019; 698: 58–63.
50.
HuangLKChaoSPHuCJ, et al.Plasma phosphorylated-tau181 is a predictor of post-stroke cognitive impairment: a longitudinal study. Front Aging Neurosci2022; 14: 889101.
51.
Mohsenian SisakhtAKaramzade-ZiaratiNJahanbakhshiA, et al.Pathogenic cis p-tau levels in CSF reflects severity of traumatic brain injury. Neurol Res2022; 44: 496–502.
52.
Ramos-MiguelAGarcia-FusterMJCalladoLF, et al.Phosphorylation of FADD (Fas-associated death domain protein) at serine 194 is increased in the prefrontal cortex of opiate abusers: relation to mitogen activated protein kinase, phosphoprotein enriched in astrocytes of 15 kDa, and akt signaling pathways involved in neuroplasticity. Neuroscience2009; 161: 23–38.
53.
Garcia-FusterMJRamos-MiguelARiveroG, et al.Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers. Neuroscience2008; 157: 105–119.
54.
KochJMKellSHinze-SelchD, et al.Changes in CREB-phosphorylation during recovery from major depression. J Psychiatr Res2002; 36: 369–375.
55.
HoggSJBeavisPADawsonMA, et al.Targeting the epigenetic regulation of antitumour immunity. Nat Rev Drug Discov2020; 19: 776–800.
56.
JanelidzeSChristianBTPriceJ, et al.Detection of brain tau pathology in Down syndrome using plasma biomarkers. JAMA Neurol2022; 79: 797–807.
57.
ZhangHZhengJWangR, et al.Serum phosphorylated neurofilament heavy subunit-H, a potential predictive biomarker for postoperative cognitive dysfunction in elderly subjects undergoing hip joint arthroplasty. J Arthroplasty2019; 34: 1602–1605.
58.
ScheltensPDe StrooperBKivipeltoM, et al.Alzheimer's disease. Lancet2021; 397: 1577–1590.
59.
KirbyBAMerrilCRGhanbariH, et al.Heat shock proteins protect against stress-related phosphorylation of tau in neuronal PC12 cells that have acquired thermotolerance. J Neurosci1994; 14: 5687–5693.
60.
YoungZTMokSAGestwickiJE. Therapeutic strategies for restoring tau homeostasis. Cold Spring Harb Perspect Med2018; 8: a024612.
61.
ChenYXuJZhouX, et al.Changes of protein phosphorylation are associated with synaptic functions during the early stage of Alzheimer's disease. ACS Chem Neurosci2019; 10: 3986–3996.
62.
IslamMSNolteHJacobW, et al.Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease. Hum Mol Genet2016; 25: 5365–5382.
63.
HeFQiGZhangQ, et al.Quantitative phosphoproteomic analysis in alpha-synuclein transgenic mice reveals the involvement of aberrant p25/Cdk5 signaling in early-stage Parkinson's disease. Cell Mol Neurobiol2020; 40: 897–909.
64.
TriplettJCZhangZSultanaR, et al.Quantitative expression proteomics and phosphoproteomics profile of brain from PINK1 knockout mice: insights into mechanisms of familial Parkinson's disease. J Neurochem2015; 133: 750–765.
65.
AuburgerGGispertSTorres-OdioS, et al.SerThr-phosphoproteome of brain from aged PINK1-KO+A53T-SNCA mice reveals pT1928-MAP1B and pS3781-ANK2 deficits, as hub between autophagy and synapse changes. Int J Mol Sci2019; 20: 3284.
66.
TenreiroSEckermannKOuteiroTF. Protein phosphorylation in neurodegeneration: friend or foe?Front Mol Neurosci2014; 7: 42.
67.
ChinLSLiL. Ubiquitin phosphorylation in Parkinson's disease: implications for pathogenesis and treatment. Transl Neurodegener2016; 5: 1.
68.
AtwalRSDesmondCRCaronN, et al.Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat Chem Biol2011; 7: 453–460.
69.
ZalaDColinERangoneH, et al.Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet2008; 17: 3837–3846.
70.
MetzlerMGanLMazareiG, et al.Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J Neurosci2010; 30: 14318–14329.
71.
SawantNReddyPH. Role of phosphorylated tau and glucose synthase kinase 3 beta in Huntington's disease progression. J Alzheimers Dis2019; 72: S177–S191.
72.
NiheiKKowallNW. Neurofilament and neural cell adhesion molecule immunocytochemistry of Huntington's disease striatum. Ann Neurol1992; 31: 59–63.
73.
LievensJCWoodmanBMahalA, et al.Abnormal phosphorylation of synapsin I predicts a neuronal transmission impairment in the R6/2 Huntington's disease transgenic mice. Mol Cell Neurosci2002; 20: 638–648.
74.
XuQHuangSSongM, et al.Synaptic mutant huntingtin inhibits synapsin-1 phosphorylation and causes neurological symptoms. J Cell Biol2013; 202: 1123–1138.
75.
SchmidtMECaronNSAlyAE, et al.DAPK1 Promotes extrasynaptic GluN2B phosphorylation and striatal spine instability in the YAC128 mouse model of Huntington disease. Front Cell Neurosci2020; 14: 590569.
76.
JoyceNCCarterGT. Electrodiagnosis in persons with amyotrophic lateral sclerosis. PM R2013; 5: S89–S95.
77.
TurnerMRBowserRBruijnL, et al.Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener2013; 14: 19–32.
78.
VejuxANamsiANuryT, et al.Biomarkers of amyotrophic lateral sclerosis: current status and interest of oxysterols and phytosterols. Front Mol Neurosci2018; 11: 12.
79.
RenYLiSChenS, et al.TDP-43 and Phosphorylated TDP-43 levels in paired plasma and CSF samples in amyotrophic lateral sclerosis. Front Neurol2021; 12: 663637.
80.
AyakiTItoHKomureO, et al.Multiple proteinopathies in familial ALS cases with optineurin mutations. J Neuropathol Exp Neurol2018; 77: 128–138.
81.
StevensCHGuthrieNJvan RoijenM, et al.Increased tau phosphorylation in motor neurons from clinically pure sporadic amyotrophic lateral sclerosis patients. J Neuropathol Exp Neurol2019; 78: 605–614.
82.
PetrozzielloTAmaralACDujardinS, et al.Novel genetic variants in MAPT and alterations in tau phosphorylation in amyotrophic lateral sclerosis post-mortem motor cortex and cerebrospinal fluid. Brain Pathol2022; 32: e13035.
83.
HecklerIVenkataramanI. Phosphorylated neurofilament heavy chain: a potential diagnostic biomarker in amyotrophic lateral sclerosis. J Neurophysiol2022; 127: 737–745.
84.
De SchaepdryverMJerominAGilleB, et al.Comparison of elevated phosphorylated neurofilament heavy chains in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry2018; 89: 367–373.
85.
BoylanKBGlassJDCrookJE, et al.Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry2013; 84: 467–472.
86.
BruggeJSEriksonRL. Identification of a transformation-specific antigen induced by an avian sarcoma virus. Nature1977; 269: 346–348.
87.
ImamuraKIzumiYWatanabeA, et al.The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci Transl Med2017; 9: eaaf3962.
88.
YangJHamadeMWuQ, et al.Current and future biomarkers in multiple sclerosis. Int J Mol Sci2022; 23: 5877.
89.
AndersonJMPataniRReynoldsR, et al.Abnormal tau phosphorylation in primary progressive multiple sclerosis. Acta Neuropathol2010; 119: 591–600.
90.
AndersonJMHamptonDWPataniR, et al.Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. Brain2008; 131: 1736–1748.
91.
SchirmerLAntelJPBruckW, et al.Axonal loss and neurofilament phosphorylation changes accompany lesion development and clinical progression in multiple sclerosis. Brain Pathol2011; 21: 428–440.
92.
CantoEIsobeNDidonnaA, et al.Aberrant STAT phosphorylation signaling in peripheral blood mononuclear cells from multiple sclerosis patients. J Neuroinflammation2018; 15: 72.
93.
OktelikFBYilmazVTurkogluR, et al.Expression of Akt1 and p-Akt1 in peripheral T cell subsets of multiple sclerosis patients. Acta Neurol Belg2021; 121: 1777–1782.
94.
WuZLiXZengM, et al.Alpha-synuclein alterations in red blood cells of peripheral blood after acute ischemic stroke. Int J Clin Exp Pathol2019; 12: 1757–1763.
95.
TakagiN. Protein tyrosine phosphorylation in the ischemic brain. J Pharmacol Sci2014; 125: 333–339.
96.
MurotomiKTakagiNTakayanagiG, et al.Mglur1 antagonist decreases tyrosine phosphorylation of NMDA receptor and attenuates infarct size after transient focal cerebral ischemia. J Neurochem2008; 105: 1625–1634.
97.
TakagiNShinnoKTevesL, et al.Transient ischemia differentially increases tyrosine phosphorylation of NMDA receptor subunits 2A and 2B. J Neurochem1997; 69: 1060–1065.
98.
DuCPGaoJTaiJM, et al.Increased tyrosine phosphorylation of PSD-95 by Src family kinases after brain ischaemia. Biochem J2009; 417: 277–285.
99.
TotsukawaGYamakitaYYamashiroS, et al.Distinct roles of ROCK (Rho-kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. J Cell Biol2000; 150: 797–806.
100.
FeskeSKSorondFAHendersonGV, et al.Increased leukocyte ROCK activity in patients after acute ischemic stroke. Brain Res2009; 1257: 89–93.
101.
BolayHGursoy-OzdemirYSaraY, et al.Persistent defect in transmitter release and synapsin phosphorylation in cerebral cortex after transient moderate ischemic injury. Stroke2002; 33: 1369–1375.
102.
LiuJZhouXLiQ, et al.Role of phosphorylated HDAC4 in stroke-induced angiogenesis. Biomed Res Int2017; 2017: 2957538.
103.
YangWJChenWChenL, et al.Involvement of tau phosphorylation in traumatic brain injury patients. Acta Neurol Scand2017; 135: 622–627.
104.
ShibahashiKDoiTTanakaS, et al.The serum phosphorylated neurofilament heavy subunit as a predictive marker for outcome in adult patients after traumatic brain injury. J Neurotrauma2016; 33: 1826–1833.
105.
OtaniNMorimotoYKinoshitaM, et al.Serial changes in serum phosphorylated neurofilament and value for prediction of clinical outcome after traumatic brain injury. Surg Neurol Int2020; 11: 387.
106.
GatsonJWBarillasJHynanLS, et al.Detection of neurofilament-H in serum as a diagnostic tool to predict injury severity in patients who have suffered mild traumatic brain injury. J Neurosurg2014; 121: 1232–1238.
107.
ZhangXChenYIkonomovicMD, et al.Increased phosphorylation of protein kinase B and related substrates after traumatic brain injury in humans and rats. J Cereb Blood Flow Metab2006; 26: 915–926.
108.
YoonYKimSSeolY, et al.Increases of phosphorylated tau (Ser202/Thr205) in the olfactory regions are associated with impaired EEG and olfactory behavior in traumatic brain injury mice. Biomedicines2022; 10: 865.
109.
HayesJPLogueMWSadehN, et al.Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer's disease. Brain2017; 140: 813–825.
110.
FrantsevaMVKokarovtsevaLNausCG, et al.Specific gap junctions enhance the neuronal vulnerability to brain traumatic injury. J Neurosci2002; 22: 644–653.
111.
ChenWGuoYYangW, et al.Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release. J Neurophysiol2018; 119: 305–311.
112.
WangYSawyerTWTseYC, et al.Primary blast-induced changes in Akt and GSK(3beta) phosphorylation in rat hippocampus. Front Neurol2017; 8: 413.
113.
LiuWLiuXYangH, et al.Phosphorylated retinoblastoma protein (p-Rb) is involved in neuronal apoptosis after traumatic brain injury in adult rats. J Mol Histol2013; 44: 147–158.
114.
TorregrossaMMMacDonaldMStoneKL, et al.Phosphoproteomic analysis of cocaine memory extinction and reconsolidation in the nucleus accumbens. Psychopharmacology (Berl)2019; 236: 531–543.
115.
Ferrer-AlconMGarcia-SevillaJAJaquetPE, et al.Regulation of nonphosphorylated and phosphorylated forms of neurofilament proteins in the prefrontal cortex of human opioid addicts. J Neurosci Res2000; 61: 338–349.
116.
KovacsGGHorvathMCMajtenyiK, et al.Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions. Neurobiol Aging2015; 36: 3100–3107.
117.
ZhuHZhuangDLouZ, et al.Akt and its phosphorylation in nucleus accumbens mediate heroin-seeking behavior induced by cues in rats. Addict Biol2021; 26: e13013.
118.
AberoumandiSMVousooghiNTabriziBA, et al.Heroin-based crack induces hyperalgesia through beta-arrestin 2 redistribution and phosphorylation of Erk1/2 and JNK in the periaqueductal gray area. Neurosci Lett2019; 698: 133–139.
119.
EdwardsSGrahamDLWhislerKN, et al.Phosphorylation of GluR1, ERK, and CREB during spontaneous withdrawal from chronic heroin self-administration. Synapse2009; 63: 224–235.
120.
SunAZhuangDZhuH, et al.Decrease of phosphorylated CREB and ERK in nucleus accumbens is associated with the incubation of heroin seeking induced by cues after withdrawal. Neurosci Lett2015; 591: 166–170.
121.
De WeerthC. Prenatal stress and the development of psychopathology: lifestyle behaviors as a fundamental part of the puzzle. Dev Psychopathol2018; 30: 1129–1144.
122.
XiaoYLuoHQYangWZ, et al.A brain signaling framework for stress-induced depression and ketamine treatment elucidated by phosphoproteomics. Front Cell Neurosci2020; 14: 48.
123.
ZhouYQiuLSterpkaA, et al.Comparative phosphoproteomic profiling of type III adenylyl cyclase knockout and control, male, and female mice. Front Cell Neurosci2019; 13: 34.
124.
BuergerKZinkowskiRTeipelSJ, et al.Differentiation of geriatric major depression from Alzheimer's disease with CSF tau protein phosphorylated at threonine 231. Am J Psychiatry2003; 160: 376–379.
125.
YamadaSYamamotoMOzawaH, et al.Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder. J Neural Transm (Vienna)2003; 110: 671–680.
126.
SimicIMaricNPMiticM, et al.Phosphorylation of leukocyte glucocorticoid receptor in patients with current episode of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry2013; 40: 281–285.
127.
JoaquimHPTalibLLForlenzaOV, et al.Long-term sertraline treatment increases expression and decreases phosphorylation of glycogen synthase kinase-3B in platelets of patients with late-life major depression. J Psychiatr Res2012; 46: 1053–1058.
128.
ZhangZZhangPQiGJ, et al.CDK5-mediated Phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress. Biochim Biophys Acta Mol Basis Dis2018; 1864: 533–541.
129.
TaniguchiSNakazawaTTanimuraA, et al.Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. EMBO J2009; 28: 3717–3729.
130.
ShiXZhangQLiJ, et al.Disrupting phosphorylation of tyr-1070 at GluN2B selectively produces resilience to depression-like behaviors. Cell Rep2021; 36: 109612.
PerkovicMNErjavecGNStracDS, et al.Theranostic biomarkers for schizophrenia. Int J Mol Sci2017; 18: 733.
133.
SheltonMANewmanJTGuH, et al.Loss of microtubule-associated protein 2 immunoreactivity linked to dendritic spine loss in schizophrenia. Biol Psychiatry2015; 78: 374–385.
134.
McKinneyBCMacDonaldMLNewmanJT, et al.Density of small dendritic spines and microtubule-associated-protein-2 immunoreactivity in the primary auditory cortex of subjects with schizophrenia. Neuropsychopharmacology2019; 44: 1055–1061.
135.
GrubishaMJSunXMacDonaldML, et al.MAP2 Is differentially phosphorylated in schizophrenia, altering its function. Mol Psychiatry2021; 26: 5371–5388.
136.
TiwariVKStadlerMBWirbelauerC, et al.A chromatin-modifying function of JNK during stem cell differentiation. Nat Genet2011; 44: 94–100.
137.
JarosJAJMartins-de-SouzaDRahmouneH, et al.Protein phosphorylation patterns in serum from schizophrenia patients and healthy controls. J Proteomics2012; 76: 43–55.
138.
San-MartinRCastroLAMenezesPR, et al.Meta-analysis of sensorimotor gating deficits in patients with schizophrenia evaluated by prepulse inhibition test. Schizophr Bull2020; 46: 1482–1497.
139.
McClatchyDBSavasJNMartinez-BartolomeS, et al.Global quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex. Mol Psychiatry2016; 21: 205–215.
140.
ShenWLuKWangJ, et al.Activation of mTOR signaling leads to orthopedic surgery-induced cognitive decline in mice through beta-amyloid accumulation and tau phosphorylation. Mol Med Rep2016; 14: 3925–3934.
141.
TianXSTongYWLiZQ, et al.Surgical stress induces brain-derived neurotrophic factor reduction and postoperative cognitive dysfunction via glucocorticoid receptor phosphorylation in aged mice. Cns Neurosci Ther2015; 21: 398–409.
142.
BueeLTroquierLBurnoufS, et al.From tau phosphorylation to tau aggregation: what about neuronal death?Biochem Soc T2010; 38: 967–972.
143.
CaoMFangJWangX, et al.Activation of AMP-activated protein kinase (AMPK) aggravated postoperative cognitive dysfunction and pathogenesis in aged rats. Brain Res2018; 1684: 21–29.
144.
Le FrecheHBrouilletteJFernandez-GomezFJ, et al.Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology2012; 116: 779–787.
145.
EveredLSilbertBScottDA, et al.Cerebrospinal fluid biomarker for Alzheimer disease predicts postoperative cognitive dysfunction. Anesthesiology2016; 124: 353–361.
146.
JiMHYuanHMZhangGF, et al.Changes in plasma and cerebrospinal fluid biomarkers in aged patients with early postoperative cognitive dysfunction following total hip-replacement surgery. J Anesth2013; 27: 236–242.
147.
Bayona-BafaluyMPGarrido-PerezNMeadeP, et al.Down syndrome is an oxidative phosphorylation disorder. Redox Biol2021; 41: 101871.
148.
LiuTWangYWangJ, et al.DYRK1A Inhibitors for disease therapy: current status and perspectives. Eur J Med Chem2022; 229: 114062.
149.
RyooSRChoHJLeeHW, et al.Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer's disease. J Neurochem2008; 104: 1333–1344.
150.
RyuYSParkSYJungMS, et al.Dyrk1A-mediated phosphorylation of Presenilin 1: a functional link between Down syndrome and Alzheimer's disease. J Neurochem2010; 115: 574–584.
151.
SoppaUSchumacherJFlorencio OrtizV, et al.The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation. Cell Cycle2014; 13: 2084–2100.
152.
SitzJHBaumgartelKHammerleB, et al.The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4. Neuroscience2008; 157: 596–605.
153.
AntonarakisSESkotkoBGRafiiMS, et al.Down syndrome. Nat Rev Dis Primers2020; 6: 9.
154.
CurtisMESmithTYuDH, et al.Association of retromer deficiency and tau pathology in Down syndrome. Ann Neurol2022; 91: 561–567.
155.
Mondragon-RodriguezSPerryGLuna-MunozJ, et al.Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome. Neuropathol Appl Neurobiol2014; 40: 121–135.
156.
MilenkovicIJarcJDasslerE, et al.The physiological phosphorylation of tau is critically changed in fetal brains of individuals with Down syndrome. Neuropathol Appl Neurobiol2018; 44: 314–327.
157.
GrauCAratoKFernandez-FernandezJM, et al.DYRK1A-mediated Phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors. Front Cell Neurosci2014; 8: 331.
158.
AltafajXMartinEDOrtiz-AbaliaJ, et al.Normalization of Dyrk1A expression by AAV2/1-shDyrk1A attenuates hippocampal-dependent defects in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis2013; 52: 117–127.
159.
de SalazarMGGrauCCiruelaF, et al.Phosphoproteomic Alterations of ionotropic glutamate receptors in the hippocampus of the Ts65Dn mouse model of Down syndrome. Front Mol Neurosci2018; 11: 226.
