Gene Expression of Psychiatric Disorder-related Kinesin Superfamily Proteins (Kifs) is Potentiated in Alternatively Activated Primary Cultured Microglia

Overview

Journal BMC Res Notes

Publisher Biomed Central

Date 2025 Jan 30

PMID 39885501

Authors

Suguru Iwata

Mitsuhiro Hyugaji

Yohei Soga

Momo Morikawa

Tetsuya Sasaki

Yosuke Takei

Affiliations

Soon will be listed here.

Abstract

Objective: Reactivity of microglia, the resident cells of the brain, underlies innate immune mechanisms (e.g., injury repair), and disruption of microglial reactivity has been shown to facilitate psychiatric disorder dysfunctions. Although cellular analyses based on cultured microglia have been conducted, the molecular mechanism regulating microglial polarization remains elusive. We established a primary microglia culture that enabled manipulation of the substate of cells. This allowed us to investigate the expression levels of psychiatric disorder-related Kifs messenger RNA (mRNA) in each condition. Kifs encode molecular motor proteins that transport cargo along microtubules, which are thought to dynamically reorganize during a substate change.

Results: As a candidate for a crucial Kifs gene that is associated with microglia polarization, we selected psychiatric disorder-related Kifs including Kif17. We found that the relative amounts of Kif3a, Kif17, and Kif13a mRNA were potentiated in alternatively activated microglia, whereas there were no significant changes in activated microglia. Furthermore, the microglia derived from a mouse line which possesses a mutation inducing truncated KIF17 indicated disrupted morphological phenotype of alternatively activated microglia. These results suggest that the potentiation of specific molecular motor expression is required to maintain the function of alternatively activated microglia.

References

Bohlen C, Bennett F, Tucker A, Collins H, Mulinyawe S, Barres B . Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures. Neuron. 2017; 94(4):759-773.e8. PMC: 5523817. DOI: 10.1016/j.neuron.2017.04.043. View

Mondelli V, Vernon A, Turkheimer F, Dazzan P, Pariante C . Brain microglia in psychiatric disorders. Lancet Psychiatry. 2017; 4(7):563-572. DOI: 10.1016/S2215-0366(17)30101-3. View

Ratta-Apha W, Mouri K, Boku S, Ishiguro H, Okazaki S, Otsuka I . A decrease in protein level and a missense polymorphism of KIF17 are associated with schizophrenia. Psychiatry Res. 2015; 230(2):424-9. DOI: 10.1016/j.psychres.2015.09.031. View

Ichinose S, Ogawa T, Hirokawa N . Mechanism of Activity-Dependent Cargo Loading via the Phosphorylation of KIF3A by PKA and CaMKIIa. Neuron. 2015; 87(5):1022-35. DOI: 10.1016/j.neuron.2015.08.008. View

Rosito M, Sanchini C, Gosti G, Moreno M, De Panfilis S, Giubettini M . Microglia reactivity entails microtubule remodeling from acentrosomal to centrosomal arrays. Cell Rep. 2023; 42(2):112104. PMC: 10423306. DOI: 10.1016/j.celrep.2023.112104. View

Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S . Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010; 330(6005):841-5. PMC: 3719181. DOI: 10.1126/science.1194637. View

Kettenmann H, Hanisch U, Noda M, Verkhratsky A . Physiology of microglia. Physiol Rev. 2011; 91(2):461-553. DOI: 10.1152/physrev.00011.2010. View

Hirokawa N, Niwa S, Tanaka Y . Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron. 2010; 68(4):610-38. DOI: 10.1016/j.neuron.2010.09.039. View

Setou M, Nakagawa T, Seog D, Hirokawa N . Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science. 2000; 288(5472):1796-802. DOI: 10.1126/science.288.5472.1796. View

10.

Morikawa M, Tanaka Y, Cho H, Yoshihara M, Hirokawa N . The Molecular Motor KIF21B Mediates Synaptic Plasticity and Fear Extinction by Terminating Rac1 Activation. Cell Rep. 2018; 23(13):3864-3877. DOI: 10.1016/j.celrep.2018.05.089. View

11.

Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C . Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res. 2006; 42(2):151-7. DOI: 10.1016/j.jpsychires.2006.10.013. View

12.

Yoshihara S, Jiang X, Morikawa M, Ogawa T, Ichinose S, Yabe H . Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport. Cell Rep. 2021; 35(2):108971. DOI: 10.1016/j.celrep.2021.108971. View

13.

Iwata S, Morikawa M, Takei Y, Hirokawa N . An activity-dependent local transport regulation via degradation and synthesis of KIF17 underlying cognitive flexibility. Sci Adv. 2020; 6(51). PMC: 7744090. DOI: 10.1126/sciadv.abc8355. View

14.

Krabbe G, Matyash V, Pannasch U, Mamer L, Boddeke H, Kettenmann H . Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun. 2011; 26(3):419-28. DOI: 10.1016/j.bbi.2011.12.002. View

15.

Izuo N, Nitta A . New Insights Regarding Diagnosis and Medication for Schizophrenia Based on Neuronal Synapse-Microglia Interaction. J Pers Med. 2021; 11(5). PMC: 8147599. DOI: 10.3390/jpm11050371. View

16.

Alsabban A, Morikawa M, Tanaka Y, Takei Y, Hirokawa N . Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice. EMBO J. 2019; 39(1):e101090. PMC: 6939202. DOI: 10.15252/embj.2018101090. View

17.

Fernandez-Arjona M, Grondona J, Granados-Duran P, Fernandez-Llebrez P, Lopez-Avalos M . Microglia Morphological Categorization in a Rat Model of Neuroinflammation by Hierarchical Cluster and Principal Components Analysis. Front Cell Neurosci. 2017; 11:235. PMC: 5550745. DOI: 10.3389/fncel.2017.00235. View

18.

Kurihara M, Ishiura H, Bannai T, Mitsui J, Yoshimura J, Morishita S . A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia. Intern Med. 2019; 59(6):839-842. PMC: 7118386. DOI: 10.2169/internalmedicine.3661-19. View

19.

Yilmaz M, Yalcin E, Presumey J, Aw E, Ma M, Whelan C . Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat Neurosci. 2020; 24(2):214-224. PMC: 8086435. DOI: 10.1038/s41593-020-00763-8. View

20.

Heneka M, Kummer M, Latz E . Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014; 14(7):463-77. DOI: 10.1038/nri3705. View