Pharmacological Inhibition of AQP4 Water Channel Activity Aggravates Alpha-Synuclein Pathology in the Substantia Nigra in a Rat Model of Parkinson’s Disease

• Published in: Journal of evolutionary biochemistry and physiology 2023-11, Vol.59 (6), p.2168-2178
• Main Authors: Lapshina, K. V., Khanina, M. V., Kaismanova, M. P., Ekimova, I. V.
• Format: Article
• Language: English
• Subjects: Amyloidogenesis; Animal models; Animal Physiology; Aquaporin 4; Biochemistry; Biomedical and Life Sciences; Channel gating; Confocal microscopy; Cytotoxicity; Dopamine receptors; Evolutionary Biology; Experimental Papers; Intracerebroventricular administration; Lactacystin; Life Sciences; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Parenchyma; Parkinson's disease; Pathology; Proteasome inhibitors; Proteasomes; Substantia nigra; Synuclein
• ISSN: 0022-0930; 1608-3202
• DOI: 10.1134/S0022093023060212

Alpha-synuclein misfolding, which leads to the formation of neurototoxic oligomers and aggregates, is one of the main causes of loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) during Parkinson’s disease (PD). We previously found that pharmacological inhibition of the aquaporin-4 (AQP4) water channel, involved in the mechanisms of amyloidogenic protein clearance from the brain, aggravates neurodegeneration in the nigrostriatal system, as well as the development of motor disorders, in a lactacystin model of PD. We hypothesized that the progression of neurodegenerative diseases may result from the excessive accumulation of pathological α-synuclein variants due to AQP4 inhibition. The aim of this study was to find out whether pharmacological downregulation of AQP4 activity in a rat model of preclinical stage of PD leads to an aggravation of α-synuclein pathology. The experiments were carried out on male Wistar rats. AQP4 activity was suppressed by the intracerebroventricular administration of the inhibitor TGN-020. The preclinical model of PD was reproduced by the bilateral administration of a specific proteasome inhibitor lactacystin (LC) into the SNpc. Immunoblot analysis and confocal microscopy were employed in the study. The LC model of PD was characterized by a pathological accumulation of the total water-soluble and Ser 129 -phosphorylated α-synuclein forms, as well as by the formation of insoluble α-synuclein aggregates in DA-ergic neurons of the SNpc. TGN-020 administration led to a significant aggravation of α-synuclein pathology in the LC model of PD, as manifested in a marked increase in the levels of water-soluble and modified α-synuclein forms and in a 1.9-fold increase in the SNpc level of α-synuclein aggregates. We suggest that the dysfunction of AQP4, which is involved in glymphatic system functioning, can be one of the mechanisms behind the neurodegeneration and accumulation of amyloidogenic proteins in the brain parenchyma during PD. The AQP4 water channel might be a promising candidate for a target to develop new therapeutic approaches aimed at abating cytotoxicity, as well as reducing the accumulation and spreading of α-synuclein, during the development of PD-like pathology.