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Abstract <p>The water channel aquaporin-4 (AQP4) is a key participantin the molecular and cellular mechanisms providing the eliminationof various metabolites and amyloid proteins from brain tissue. Itis assumed that AQP4 dysfunction may provoke the development ofParkinson’s disease (PD) and lead to its aggravation. The aim ofthis study was to elucidate whether downregulated AQP4 expressionin the substantia nigra pars compacta (SNpc) affects the developmentof α-synuclein pathology, neurodegeneration, and motor impairmentin a rat model of the clinical stage of PD. Experiments were carriedout on male Wistar rats aged 6–7 months. To downregulate AQP4 expressionin the SNpc, a lentiviral construct containing a nucleotide sequencethat encodes a short hairpin RNA (shRNA) interfering with naturalAQP4 mRNA and thus silencing the <i>Aqp4</i> gene(AQP4-LVC) was injected into the SNpc. To reproduce a model of theclinical stage of PD, the proteasome inhibitor lactacystin (LC) wasbilaterally injected into the SNpc four weeks following AQP4-LVCadministration. The study involved behavioral tests, immunohistochemicallabeling, and immunoblotting. AQP4-LVC application caused a 42%decrease in AQP4 protein content in the SNpc after four weeks. TheLC model of PD was characterized by the appearance of motor disorders,death of 57% of dopamine (DA)-ergic neurons in the SNpc and 56%of their axons in the striatum, attenuation of compensatory processesaimed at maintaining DA level in the nigrostriatal system, and anincrease in the content of a total water-soluble form of α-synuclein,as well as its aggregated and Ser129-phosphorylated forms. Downregulationof AQP4 expression in the SNpc in an LC model of PD exacerbatedmotor dysfunction and caused the appearance of dystrophy signs,indicating the development of a terminal phase of the clinical stageof PD. The rapid progression of parkinsonian symptoms was associatedwith enhanced neurodegeneration and the depletion of compensatoryprocesses in the nigrostriatal system, coupled with the accelerated formationof pathological α-synuclein aggregates. The obtained data indicatethat AQP4 deficiency in the SNpc accelerates the development ofParkinson’s-like pathology.</p>

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

  • 期刊论文

  • 发表日期：

    2025年10月1日

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  • K. V. Lapshina,
  • M. V. Khanina,
  • M. A. Guzeev,
  • M. P. Kaismanova,
  • I. V. Ekimova

摘要

Abstract

The water channel aquaporin-4 (AQP4) is a key participantin the molecular and cellular mechanisms providing the eliminationof various metabolites and amyloid proteins from brain tissue. Itis assumed that AQP4 dysfunction may provoke the development ofParkinson’s disease (PD) and lead to its aggravation. The aim ofthis study was to elucidate whether downregulated AQP4 expressionin the substantia nigra pars compacta (SNpc) affects the developmentof α-synuclein pathology, neurodegeneration, and motor impairmentin a rat model of the clinical stage of PD. Experiments were carriedout on male Wistar rats aged 6–7 months. To downregulate AQP4 expressionin the SNpc, a lentiviral construct containing a nucleotide sequencethat encodes a short hairpin RNA (shRNA) interfering with naturalAQP4 mRNA and thus silencing the Aqp4 gene(AQP4-LVC) was injected into the SNpc. To reproduce a model of theclinical stage of PD, the proteasome inhibitor lactacystin (LC) wasbilaterally injected into the SNpc four weeks following AQP4-LVCadministration. The study involved behavioral tests, immunohistochemicallabeling, and immunoblotting. AQP4-LVC application caused a 42%decrease in AQP4 protein content in the SNpc after four weeks. TheLC model of PD was characterized by the appearance of motor disorders,death of 57% of dopamine (DA)-ergic neurons in the SNpc and 56%of their axons in the striatum, attenuation of compensatory processesaimed at maintaining DA level in the nigrostriatal system, and anincrease in the content of a total water-soluble form of α-synuclein,as well as its aggregated and Ser129-phosphorylated forms. Downregulationof AQP4 expression in the SNpc in an LC model of PD exacerbatedmotor dysfunction and caused the appearance of dystrophy signs,indicating the development of a terminal phase of the clinical stageof PD. The rapid progression of parkinsonian symptoms was associatedwith enhanced neurodegeneration and the depletion of compensatoryprocesses in the nigrostriatal system, coupled with the accelerated formationof pathological α-synuclein aggregates. The obtained data indicatethat AQP4 deficiency in the SNpc accelerates the development ofParkinson’s-like pathology.