Aquaporin-4 Knockdown in the Substantia Nigra Exacerbates α-Synuclein Pathology, Neurodegeneration, and Motor Dysfunction in a Rat Model of Parkinson's Disease

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Resumo

The water channel aquaporin-4 (AQP4) is a key participant in the molecular and cellular mechanisms that provide the removal of various metabolites and amyloid proteins from brain tissue. It is assumed that AQP4 dysfunction can provoke the development of Parkinson's disease (PD) and lead to its aggravation. The aim of this study was to investigate whether decreased AQP4 expression in the substantia nigra pars compacta (SNpc) affects the development of α-synuclein pathology, neurodegeneration, and motor impairment in a rat model of clinical stage PD. Experiments were performed on male Wistar rats (6-7 months). To suppress AQP4 expression in the SNpc, a lentiviral construct containing a nucleotide sequence encoding hairpin RNA (shRNA) to AQP4 mRNA (AQP4-LVC) was injected. To reproduce the clinical stage of PD, the proteasome inhibitor lactacystin (LC) was bilaterally injected into the SNpc 4 weeks after AQP4-LVC administration. To solve the scientific task, behavioral tests, the immunohistochemical method, and immunoblotting were applied. The AQP4-LVC caused a 42% decrease in the AQP4 protein content in the SNpc 4 weeks later. The LC model of PD was characterized by the appearance of motor disorders, the death of 57% of dopamine (DA)-ergic neurons in the SNpc and 56% of their axons in the striatum, weakening of compensatory processes aimed at maintaining DA level in the nigrostriatal system, and an increase in the content of the total water-soluble form of α-synuclein and its aggregated and phosphorylated (Ser129) forms. Decreased expression of AQP4 in the LC model of PD caused aggravation of motor impairment and the appearance of signs of dystrophy, indicating the development of the terminal phase of the clinical stage of PD. The rapid increase in parkinsonism symptoms was associated with increased neurodegeneration and depletion of compensatory processes in the nigrostriatal system, associated with the acceleration of the formation of pathological aggregated forms of α-synuclein. The obtained data indicate that AQP4 deficiency in the SNpc accelerates the development of Parkinson-like pathology.

Sobre autores

K. Lapshina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: ksenia.lapshina@gmail.com
St. Petersburg, Russia

M. Khanina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

St. Petersburg, Russia

M. Guzeev

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

St. Petersburg, Russia

M. Kaismanova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

St. Petersburg, Russia

I. Ekimova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

St. Petersburg, Russia

Bibliografia

  1. Gouda NA, Elkamhawy A, Cho J (2022) Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update. Biomedicines 10(2): 371. https://doi.org/10.3390/biomedicines10020371
  2. Raza C, Anjum R, Shakeel NUA (2019). Parkinson's disease: Mechanisms, translational models and management strategies. Life Sci 226: 77–90. https://doi.org/10.1016/j.lfs.2019.03.057
  3. Ou Z, Pan J, Tang S, Duan D, Yu D, Nong H, Wang Z (2021) Global trends in the incidence, prevalence, and years lived with disability of Parkinson's disease in 204 countries/territories from 1990 to 2019. Front Public Health 9: 776847. https://doi.org/10.3389/fpubh.2021.776847
  4. McFarthing K, Buff S, Rafaloff G, Pitzer K, Fiske B, Navangul A, Beissert K, Pilcicka A, Fuest R, Wyse RK, Stott SRW (2024) Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2024 Update. J Parkinsons Dis 14(5): 899–912. https://doi.org/10.3233/JPD-240272
  5. Paulėkas E, Vanagas T, Lagunavičius S, Pajėdienė E, Petrikonis K, Rastenytė D (2024). Navigating the Neurobiology of Parkinson's: The Impact and Potential of α-Synuclein. Biomedicines 12(9): 2121. https://doi.org/10.3390/biomedicines12092121
  6. Hamazaki J, Murata S (2024) Relationships between protein degradation, cellular senescence, and organismal aging. J Biochem 175(5): 473–480. https://doi.org/10.1093/jb/mvae016
  7. Mader S, Brimberg L (2019) Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells 8(2): 90. https://doi.org/10.3390/cells8020090
  8. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4(147): 147ra111. https://doi.org/10.1126/scitranslmed.3003748
  9. Lian X, Liu Z, Gan Z, Yan Q, Tong L, Qiu L, Liu Y, Chen JF, Li Z (2026 Epub 2025 Jan 13) Targeting the glymphatic system to promote α-synuclein clearance: А novel therapeutic strategy for Parkinson's disease. Neural Regen Res 21(1): 233–247. https://doi.org/10.4103/NRR.NRR-D-24-00764
  10. Semyachkina-Glushkovskaya O, Postnov D, Kurths J (2018) Blood Brain Barrier, Lymphatic Clearance, and Recovery: Ariadne's Thread in Labyrinths of Hypotheses. Int J Mol Sci 19(12): 3818. https://doi.org/10.3390/ijms19123818
  11. Nagelhus EA, Ottersen OP (2013) Physiological roles of aquaporin-4 in brain. Physiol Rev 93(4): 1543–1562. https://doi.org/10.1152/physrev.00011.2013
  12. Vandebroek A, Yasui M (2020) Regulation of AQP4 in the Central Nervous System. Int J Mol Sci 21(5): 1603. https://doi.org/10.3390/ijms21051603
  13. Semyachkina-Glushkovskaya OV, Postnov DE, Khorovodov AP, Navolokin NA, Kurthz JHG (2023) Lymphatic drainage system of the brain: А new player in neuroscience. J Evol Biochem Physiol 59: 1–19. https://doi.org/10.1134/S0022093023010015
  14. Zhang Q, Niu Y, Li Y, Xia C, Chen Z, Chen Y, Feng H (2025) Meningeal lymphatic drainage: Novel insights into central nervous system disease Signal Transduct Target Ther 10(1): 142. https://doi.org/10.1038/s41392-025-02177-z
  15. Ding Z, Fan X, Zhang Y, Yao M, Wang G, Dong Y, Liu J, Song W (2023) The glymphatic system: a new perspective on brain diseases. Front Aging Neurosci 15: 1179988. https://doi.org/10.3389/fnagi.2023.1179988
  16. Miao A, Luo T, Hsieh B, Edge CJ, Gridley M, Wong RTC, Constandinou TG, Wisden W, Franks NP (2024) Brain clearance is reduced during sleep and anesthesia. Nat Neurosci 27(6): 1046–1050. Erratum in: (2024) Nat Neurosci 27(7): 1425. https://doi.org/10.1038/s41593-024-01638-y
  17. Hoshi A, Tsunoda A, Tada M, Nishizawa M, Ugawa Y, Kakita A (2017) Expression of aquaporin 1 and aquaporin 4 in the temporal neocortex of patients with Parkinson's Disease. Brain Pathol 27(2): 160–168. https://doi.org/10.1111/bpa.12369
  18. Fang Y, Dai S, Jin C, Si X, Gu L, Song Z, Gao T, Chen Y, Yan Y, Yin X, Pu J, Zhang B (2022) aquaporin-4 polymorphisms are associated with cognitive performance in Parkinson's disease. Front Aging Neurosci 13: 740491. https://doi.org/10.3389/fnagi.2021.740491
  19. Sun X, Tian Q, Yang Z, Liu Y, Li C, Hou B, Xie A (2023) Association of AQP4 single nucleotide polymorphisms (rs335929 and rs2075575) with Parkinson's disease: A case-control study. Neurosci Lett 797: 137062. https://doi.org/10.1016/j.neulet.2023.137062
  20. Meinhold L, Gennari AG, Baumann-Vogel H, Werth E, Schreiner SJ, Ineichen C, Baumann CR, O'Gorman Tuura R (2025) T2 MRI visible perivascular spaces in Parkinson's disease: Сlinical significance and association with polysomnography measured sleep. Sleep 48(1): zsae233. https://doi.org/10.1093/sleep/zsae233
  21. Xing Y, Lin M, Li J, Huang X, Yan L, Ren J, Zhou H, Chen S, Cao Y, Huang P, Liu W (2025) Perivascular space fluid diffusivity predicts clinical deterioration in prodromal and early-stage Parkinson's disease. NPJ Parkinsons Dis 11(1): 169. https://doi.org/10.1038/s41531-025-01036-6
  22. Cui H, Wang W, Zheng X, Xia D, Liu H, Qin C, Tian H, Teng J (2021) Decreased AQP4 expression aggravates ɑ-synuclein pathology in Parkinson's disease mice, possibly via impaired glymphatic clearance. J Mol Neurosci 71: 2500–2513. https://doi.org/10.1007/s12031-021-01836-4
  23. Xue X, Zhang W, Zhu J, Chen X, Zhou S, Xu Z, Hu G, Su C (2019) Aquaporin-4 deficiency reduces TGF-β1 in mouse midbrains and exacerbates pathology in experimental Parkinson’s disease. J Cell Mol Med 23: 2568–2582. https://doi.org/10.1111/jcmm.14147
  24. Prydz A, Stahl K, Zahl S, Skauli N, Skare Ø, Ottersen OP, Amiry-Moghaddam M (2020) Pro-Inflammatory Role of AQP4 in Mice Subjected to Intrastriatal Injections of the Parkinsonogenic Toxin MPP. Cells 9(11): 2418. https://doi.org/10.3390/cells9112418
  25. Lapshina KV, Ekimova IV (2024) Aquaporin-4 and Parkinson's Disease. Int J Mol Sci 25(3): 1672. https://doi.org/10.3390/ijms25031672
  26. Zhang Y, Zhang C, He XZ, Li ZH, Meng JC, Mao RT, Li X, Xue R, Gui Q, Zhang GX, Wang LH (2023) Interaction between the glymphatic system and α-synuclein in Parkinson's disease. Mol Neurobiol 60(4): 2209–2222. https://doi.org/10.1007/s12035-023-03212-2
  27. Lapshina KV, Abramova YY, Guzeev MA, Ekimova IV (2022) TGN-020, an inhibitor of the water channel aquaporin-4, accelerates nigrostriatal neurodegeneration in the rat model of Parkinson’s disease. J Evol Biochem Physiol 58: 2035–2047. https://doi.org/10.1134/S0022093022060308
  28. Lapshina KV, Khanina MV, Kaismanova MP, Ekimova IV (2023) Pharmacological Inhibition of AQP4 Water Channel Activity Aggravates of Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s Disease. J Evol Biochem Physiol 59: 2168–2178. https://doi.org/10.1134/S0022093023060212
  29. McNaught KS, Perl DP, Brownell AL, Olanow CW (2004) Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann Neurol 56(1): 149–162. https://doi.org/10.1002/ana.20186
  30. Ekimova IV, Belan DV, Lapshina KV, Pastukhov YuF (2023) The use of the proteasome inhibitor lactacystin for modeling Parkinson’s disease: Early neurophysiological biomarkers and candidates for intranigral and extranigral neuroprotection. In: Handbook of Animal Models in Neurological Disorders. Martin CR, Patel VB, Preedy VR (eds) Acad Press, Elsevier, pp 507–523.
  31. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. 6th Edition. Acad. Press, San Diego.
  32. Kane JR, Ciucci MR, Jacobs AN, Tews N, Russell JA, Ahrens AM, Ma ST, Britt JM, Cormack LK, Schallert T (2011) Assessing the role of dopamine in limb and cranial-oromotor control in a rat model of Parkinson's disease. J Сommunicat Disord 44(5): 529–537. https://doi.org/10.1016/j.jcomdis.2011.04.005
  33. Seibenhener ML, Wooten MC (2015) Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp 96: e52434. https://doi.org/10.3791/52434
  34. Fleming SM, Ekhator OR, Ghisays V (2013) Assessment of sensorimotor function in mouse models of Parkinson's disease. J Vis Exp 76: 50303. https://doi.org/10.3791/50303 2
  35. Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: Тherapeutic targets and strategies. Exp Mol Med 47(3): е147. https://doi.org/10.1038/emm.2014.117
  36. Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in Parkinson's disease. J Neural Transm 38: 277–301.
  37. Thenral ST, Vanisree AJ (2012) Peripheral assessment of the genes AQP4, PBP and TH in patients with Parkinson’s disease. Neurochem Res 37: 512–515. https://doi.org/10.1007/ s11064-011-0637-5
  38. Si X, Dai S, Fang Y, Tang J, Wang Z, Li Y, Song Z, Chen Y, Liu Y, Zhao G, Zhang B, Pu J (2024) Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson's disease. J Adv Res 56: 125–136. https://doi.org/10.1016/j.jare.2023.03.004
  39. Loria F, Vargas JY, Bousset L, Syan S, Salles A, Melki R, Zurzolo C (2017) α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 134: 789–808. https://doi.org/10.1007/s00401-017-1746-2
  40. Brück D, Wenning GK, Stefanova N, Fellner L (2016) Glia and alpha-synuclein in neurodegeneration: А complex interaction. Neurobiol Dis 85: 262–274. https://doi.org/10.1016/j.nbd.2015.03.003
  41. Zhang J, Yang B, Sun H, Zhou Y, Liu M, Ding J, Fang F, Fan Y, Hu G (2016) Aquaporin-4 deficiency diminishes the differential degeneration of midbrain dopaminergic neurons in experimental Parkinson's disease. Neurosci Lett 614: 7–15. https://doi.org/10.1016/j.neulet.2015.12.057

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