Map2k5-Deficient Mice Manifest Phenotypes and Pathological Changes of Dopamine Deficiency in the Central Nervous System

Overview

Journal Front Aging Neurosci

Specialty Geriatrics

Date 2021 Jun 25

PMID 34168549

Citations 4

Authors

Yumeng Huang

Pei Wang

Rodrigo Morales

Qi Luo

Jianfang Ma

Affiliations

Soon will be listed here.

Abstract

MAP2K5, a member of the MAPK family, is associated with central nervous system disorders. However, neural functional of Map2k5 from animal models were not well examined so far. Here, we established a Map2k5-targeted knockout mouse model to investigate the behavior phenotypes and its underlying molecular mechanism. Our results showed that female Map2k5 mutant mice manifested decreased circadian-dependent ambulatory locomotion, coordination, and fatigue. Male Map2k5 mutant mice displayed impairment in open field exploration and prepulse inhibition of acoustic startle response (ASR) when compared with wild-type controls. Furthermore, Map2k5 mutant mice showed a decreased dopaminergic cell survival and tyrosine hydroxylase levels in nigrostriatal pathway, indicating a crucial role of MAP2K5 in regulating dopamine system in the central nervous system. In conclusion, this is the first study demonstrating that Map2k5 mutant mice displayed phenotypes by disturbing the dopamine system in the central nervous system, implicating Map2k5 mutant mouse as a promising model for many dopamine related disorders.

Citing Articles

Unveiling the pathophysiology of restless legs syndrome through transcriptome analysis.

Mogavero M, Salemi M, Lanza G, Rinaldi A, Marchese G, Ravo M iScience. 2024; 27(4):109568.

PMID: 38617564 PMC: 11015462. DOI: 10.1016/j.isci.2024.109568.

Oscillatory Hypoxia Can Induce Senescence of Adipose-Derived Mesenchymal Stromal Cells Potentiating Invasive Transformation of Breast Epithelial Cells.

Novin A, Wali K, Pant A, Liu S, Du W, Liu Y Cancers (Basel). 2024; 16(5).

PMID: 38473331 PMC: 10930887. DOI: 10.3390/cancers16050969.

Putative Animal Models of Restless Legs Syndrome: A Systematic Review and Evaluation of Their Face and Construct Validity.

Silvani A, Ghorayeb I, Manconi M, Li Y, Clemens S Neurotherapeutics. 2022; 20(1):154-178.

PMID: 36536233 PMC: 10119375. DOI: 10.1007/s13311-022-01334-4.

Low-Dose Anti-HIV Drug Efavirenz Mitigates Retinal Vascular Lesions in a Mouse Model of Alzheimer's Disease.

El-Darzi N, Mast N, Buchner D, Saadane A, Dailey B, Trichonas G Front Pharmacol. 2022; 13:902254.

PMID: 35721135 PMC: 9198296. DOI: 10.3389/fphar.2022.902254.

References

Zou J, Pan Y, Wang Z, Chang S, Wang W, Wang X . Targeted deletion of ERK5 MAP kinase in the developing nervous system impairs development of GABAergic interneurons in the main olfactory bulb and behavioral discrimination between structurally similar odorants. J Neurosci. 2012; 32(12):4118-32. PMC: 3333842. DOI: 10.1523/JNEUROSCI.6260-11.2012. View

Cabrera-Mendoza B, Martinez-Magana J, Genis-Mendoza A, Sarmiento E, Ruiz-Ramos D, Tovilla-Zarate C . High polygenic burden is associated with blood DNA methylation changes in individuals with suicidal behavior. J Psychiatr Res. 2020; 123:62-71. DOI: 10.1016/j.jpsychires.2020.01.008. View

Allen R, Picchietti D, Garcia-Borreguero D, Ondo W, Walters A, Winkelman J . Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance. Sleep Med. 2014; 15(8):860-73. DOI: 10.1016/j.sleep.2014.03.025. View

Kang S, Lee Y, Park Y, Kim L, Lee H . Haplotype Association of the Gene with Antipsychotics-Induced Symptoms of Restless Legs Syndrome among Patients with Schizophrenia. Psychiatry Investig. 2018; 15(1):84-89. PMC: 5795036. DOI: 10.4306/pi.2018.15.1.84. View

Liu L, Cundiff P, Abel G, Wang Y, Faigle R, Sakagami H . Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortical neuronal fate. Proc Natl Acad Sci U S A. 2006; 103(25):9697-702. PMC: 1480469. DOI: 10.1073/pnas.0603373103. View

Jo M, Chung A, Yachie N, Seo M, Jeon H, Nam Y . Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target. Genome Res. 2017; 27(9):1487-1500. PMC: 5580709. DOI: 10.1101/gr.211649.116. View

Parmar M, Jaumotte J, Zigmond M, Cavanaugh J . ERK1, 2, and 5 expression and activation in dopaminergic brain regions during postnatal development. Int J Dev Neurosci. 2015; 46:44-50. DOI: 10.1016/j.ijdevneu.2015.06.009. View

Simoes A, Pereira D, Gomes S, Brito H, Carvalho T, French A . Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activation. Cell Death Dis. 2015; 6:e1718. PMC: 4650550. DOI: 10.1038/cddis.2015.83. View

Tapias-Espinosa C, Rio-Alamos C, Sanchez-Gonzalez A, Oliveras I, Sampedro-Viana D, Castillo-Ruiz M . Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume. Neuropsychopharmacology. 2019; 44(11):1975-1984. PMC: 6784988. DOI: 10.1038/s41386-019-0392-x. View

10.

Yeomans J, Li L, Scott B, Frankland P . Tactile, acoustic and vestibular systems sum to elicit the startle reflex. Neurosci Biobehav Rev. 2002; 26(1):1-11. DOI: 10.1016/s0149-7634(01)00057-4. View

11.

Gan-Or Z, Alcalay R, Bar-Shira A, Leblond C, Postuma R, Ben-Shachar S . Genetic markers of Restless Legs Syndrome in Parkinson disease. Parkinsonism Relat Disord. 2015; 21(6):582-5. PMC: 4441838. DOI: 10.1016/j.parkreldis.2015.03.010. View

12.

Kim B, Jeong K, Kim J, Jin M, Kim J, Lee M . Pathogenic Upregulation of Glial Lipocalin-2 in the Parkinsonian Dopaminergic System. J Neurosci. 2016; 36(20):5608-22. PMC: 6601774. DOI: 10.1523/JNEUROSCI.4261-15.2016. View

13.

Korner G, Noain D, Ying M, Hole M, Flydal M, Scherer T . Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency. Brain. 2015; 138(Pt 10):2948-63. DOI: 10.1093/brain/awv224. View

14.

Cavanaugh J, Jaumotte J, Lakoski J, Zigmond M . Neuroprotective role of ERK1/2 and ERK5 in a dopaminergic cell line under basal conditions and in response to oxidative stress. J Neurosci Res. 2006; 84(6):1367-75. DOI: 10.1002/jnr.21024. View

15.

ENGLISH J, Pearson G, Baer R, Cobb M . Identification of substrates and regulators of the mitogen-activated protein kinase ERK5 using chimeric protein kinases. J Biol Chem. 1998; 273(7):3854-60. DOI: 10.1074/jbc.273.7.3854. View

16.

Liu F, Zhang H, Song H . Upregulation of MEK5 by Stat3 promotes breast cancer cell invasion and metastasis. Oncol Rep. 2016; 37(1):83-90. DOI: 10.3892/or.2016.5256. View

17.

Li T, Pan Y, Wang W, Abel G, Zou J, Xu L . Targeted deletion of the ERK5 MAP kinase impairs neuronal differentiation, migration, and survival during adult neurogenesis in the olfactory bulb. PLoS One. 2013; 8(4):e61948. PMC: 3632513. DOI: 10.1371/journal.pone.0061948. View

18.

Dinev D, Jordan B, Neufeld B, Lee J, Lindemann D, Rapp U . Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. EMBO Rep. 2001; 2(9):829-34. PMC: 1084032. DOI: 10.1093/embo-reports/kve177. View

19.

Liu Y, Yang Y, Wan F, Tung C . Importance of intervention timing in the effectiveness of antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry. 2017; 81:493-500. DOI: 10.1016/j.pnpbp.2017.02.003. View

20.

Langley M, Ghosh A, Charli A, Sarkar S, Ay M, Luo J . Mito-Apocynin Prevents Mitochondrial Dysfunction, Microglial Activation, Oxidative Damage, and Progressive Neurodegeneration in MitoPark Transgenic Mice. Antioxid Redox Signal. 2017; 27(14):1048-1066. PMC: 5651937. DOI: 10.1089/ars.2016.6905. View