Unilateral RNurr1-V5 Transgene Expression in Nigral Dopaminergic Neurons Mitigates Bilateral Neuropathology and Behavioral Deficits in Parkinsonian Rats with α-synucleinopathy

JOURNAL/nrgr/04.03/01300535-202409000-00039/figure1/v/2024-01-16T170235Z/r/image-tiff Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson's disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson's disease.

Citing Articles

27-Hydroxymangiferolic Acid Extends Lifespan and Improves Neurodegeneration in by Activating Nuclear Receptors.

Gao X, Yu J, Li Y, Shi H, Zhang L, Fang M Molecules. 2025; 30(5).

PMID: 40076235 PMC: 11902184. DOI: 10.3390/molecules30051010.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease.

Zhou S, Li T, Zhang W, Wu J, Hong H, Quan W Neural Regen Res. 2024; 20(8):2361-2372.

PMID: 39359093 PMC: 11759022. DOI: 10.4103/NRR.NRR-D-23-01684.

Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation.

Mascotte-Cruz J, Vera A, Leija L, Lopez-Salas F, Gradzielski M, Koetz J Discov Nano. 2024; 19(1):60.

PMID: 38564106 PMC: 10987469. DOI: 10.1186/s11671-024-04005-9.

References

de Pins B, Cifuentes-Diaz C, Farah A, Lopez-Molina L, Montalban E, Sancho-Balsells A . Conditional BDNF Delivery from Astrocytes Rescues Memory Deficits, Spine Density, and Synaptic Properties in the 5xFAD Mouse Model of Alzheimer Disease. J Neurosci. 2019; 39(13):2441-2458. PMC: 6435824. DOI: 10.1523/JNEUROSCI.2121-18.2019. View

Duffy M, Collier T, Patterson J, Kemp C, Luk K, Tansey M . Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. J Neuroinflammation. 2018; 15(1):129. PMC: 5930695. DOI: 10.1186/s12974-018-1171-z. View

Hammond S, Popichak K, Li X, Hunt L, Richman E, Damale P . The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. J Pharmacol Exp Ther. 2018; 365(3):636-651. PMC: 5941193. DOI: 10.1124/jpet.117.246389. View

Lopez-Salas F, Nadella R, Maldonado-Berny M, Escobedo-Sanchez M, Fiorentino-Perez R, Gatica-Garcia B . Synthetic Monopartite Peptide That Enables the Nuclear Import of Genes Delivered by the Neurotensin-Polyplex Vector. Mol Pharm. 2020; 17(12):4572-4588. DOI: 10.1021/acs.molpharmaceut.0c00755. View

Montarolo F, Raffaele C, Perga S, Martire S, Finardi A, Furlan R . Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in mice. PLoS One. 2014; 9(9):e108791. PMC: 4181297. DOI: 10.1371/journal.pone.0108791. View

Le W, Conneely O, Zou L, He Y, Saucedo-Cardenas O, Jankovic J . Selective agenesis of mesencephalic dopaminergic neurons in Nurr1-deficient mice. Exp Neurol. 1999; 159(2):451-8. DOI: 10.1006/exnr.1999.7191. View

Soto-Rojas L, Martinez-Davila I, Luna-Herrera C, Gutierrez-Castillo M, Lopez-Salas F, Gatica-Garcia B . Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat. Acta Neuropathol Commun. 2020; 8(1):56. PMC: 7178762. DOI: 10.1186/s40478-020-00933-6. View

Nadella R, Voutilainen M, Saarma M, Gonzalez-Barrios J, Leon-Chavez B, Duenas Jimenez J . Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra. J Neuroinflammation. 2014; 11:209. PMC: 4275959. DOI: 10.1186/s12974-014-0209-0. View

Chu Y, Muller S, Tavares A, Barret O, Alagille D, Seibyl J . Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes. Brain. 2019; 142(11):3565-3579. PMC: 7962904. DOI: 10.1093/brain/awz296. View

10.

Su Y, Chen Z, Du H, Liu R, Wang W, Li H . Silencing miR-21 induces polarization of astrocytes to the A2 phenotype and improves the formation of synapses by targeting glypican 6 the signal transducer and activator of transcription-3 pathway after acute ischemic spinal cord injury. FASEB J. 2019; 33(10):10859-10871. DOI: 10.1096/fj.201900743R. View

11.

Conway J, Ince S, Black S, Kramer E . GDNF/RET signaling in dopamine neurons in vivo. Cell Tissue Res. 2020; 382(1):135-146. DOI: 10.1007/s00441-020-03268-9. View

12.

Gava-Junior G, Ferreira S, Roque C, Mendes-Oliveira J, Serrenho I, Pinto N . High-frequency repetitive magnetic stimulation rescues ischemia-injured neurons through modulation of glial-derived neurotrophic factor present in the astrocyte's secretome. J Neurochem. 2022; 164(6):813-828. DOI: 10.1111/jnc.15740. View

13.

Kadkhodaei B, Alvarsson A, Schintu N, Ramskold D, Volakakis N, Joodmardi E . Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons. Proc Natl Acad Sci U S A. 2013; 110(6):2360-5. PMC: 3568335. DOI: 10.1073/pnas.1221077110. View

14.

Kim S, Cho S, Kim M, Roh S, Shin H, Suh Y . Genome-Wide Analysis Identifies NURR1-Controlled Network of New Synapse Formation and Cell Cycle Arrest in Human Neural Stem Cells. Mol Cells. 2020; 43(6):551-571. PMC: 7332357. DOI: 10.14348/molcells.2020.0071. View

15.

Jacobsen K, MacDonald H, Lemonde S, Daigle M, Grimes D, Bulman D . A Nurr1 point mutant, implicated in Parkinson's disease, uncouples ERK1/2-dependent regulation of tyrosine hydroxylase transcription. Neurobiol Dis. 2007; 29(1):117-22. DOI: 10.1016/j.nbd.2007.08.003. View

16.

Kim H, Lee S, Lim J, Chung S, Koo T, Ji Y . ERRγ ligand HPB2 upregulates BDNF-TrkB and enhances dopaminergic neuronal phenotype. Pharmacol Res. 2021; 165:105423. DOI: 10.1016/j.phrs.2021.105423. View

17.

Gamit N, Dharmarajan A, Sethi G, Warrier S . Want of Wnt in Parkinson's disease: Could sFRP disrupt interplay between Nurr1 and Wnt signaling?. Biochem Pharmacol. 2023; 212:115566. DOI: 10.1016/j.bcp.2023.115566. View

18.

Shanley M, Miura Y, Guevara C, Onoichenco A, Kore R, Ustundag E . Estrous Cycle Mediates Midbrain Neuron Excitability Altering Social Behavior upon Stress. J Neurosci. 2022; 43(5):736-748. PMC: 9899085. DOI: 10.1523/JNEUROSCI.1504-22.2022. View

19.

Aranda-Barradas M, Marquez M, Quintanar L, Santoyo-Salazar J, Espadas-Alvarez A, Martinez-Fong D . Development of a Parenteral Formulation of NTS-Polyplex Nanoparticles for Clinical Purpose. Pharmaceutics. 2018; 10(1). PMC: 5874818. DOI: 10.3390/pharmaceutics10010005. View

20.

Liddelow S, Guttenplan K, Clarke L, Bennett F, Bohlen C, Schirmer L . Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017; 541(7638):481-487. PMC: 5404890. DOI: 10.1038/nature21029. View