Abstract
More than 90% of the cases of Parkinson’s disease have unknown etiology. Gradual loss of dopaminergic neurons of substantia nigra is the main cause of morbidity in this disease. External factors such as environmental toxins are believed to play a role in the cell loss, although the cause of the selective vulnerability of dopaminergic neurons remains unknown. We have previously shown that aquaglyceroporin AQP9 is expressed in dopaminergic neurons and astrocytes of rodent brain. AQP9 is permeable to a broad spectrum of substrates including purines, pyrimidines, and lactate, in addition to water and glycerol. Here we test our hypothesis that AQP9 serves as an influx route for exogenous toxins and, hence, may contribute to the selective vulnerability of nigral dopaminergic (tyrosine hydroxylase-positive) neurons. Using Xenopus oocytes injected with Aqp9 cRNA, we show that AQP9 is permeable to the parkinsonogenic toxin 1-methyl-4-phenylpyridinium (MPP+). Stable expression of AQP9 in HEK cells increases their vulnerability to MPP+ and to arsenite—another parkinsonogenic toxin. Conversely, targeted deletion of Aqp9 in mice protects nigral dopaminergic neurons against MPP+ toxicity. A protective effect of Aqp9 deletion was demonstrated in organotypic slice cultures of mouse midbrain exposed to MPP+ in vitro and in mice subjected to intrastriatal injections of MPP+ in vivo. Seven days after intrastriatal MPP+ injections, the population of tyrosine hydroxylase-positive cells in substantia nigra is reduced by 48% in Aqp9 knockout mice compared with 67% in WT littermates. Our results show that AQP9 –selectively expressed in catecholaminergic neurons—is permeable to MPP+ and suggest that this aquaglyceroporin contributes to the selective vulnerability of nigral dopaminergic neurons by providing an entry route for parkinsonogenic toxins. To our knowledge this is the first evidence implicating a toxin permeable membrane channel in the pathophysiology of Parkinson’s disease.
Highlights
Parkinson’s disease is one of the most common neurodegenerative disorders, affecting 1–2% of the population over 50 years [1,2,3,4]
We show that stable expression of AQP9 in human embryonic kidney cells 293 (HEK) cells exacerbates their vulnerability to MPP+ and arsenite—another toxin associated with the development of PD
Earlier studies have shown that AQP9 is expressed in midbrain neurons that contain tyrosine hydroxylase (TH)—a marker of dopaminergic neurons [23,24,26,55]
Summary
Parkinson’s disease is one of the most common neurodegenerative disorders, affecting 1–2% of the population over 50 years [1,2,3,4]. This disease is characterized by loss of dopaminergic neurons in the SNpc with decreased dopamine levels in the basal ganglia [5], and is clinically manifested by motor dysfunction, including bradykinesia, resting tremor, rigidity and postural instability, and non-motor symptoms including, but not limited to, cognitive impairment, mood disorders, sleep disorders, constipation, bladder dysfunction and loss of sense of smell [6]. Mechanisms for the selective vulnerability of dopaminergic neurons to such toxins remain to be elucidated, there is ample evidence that toxin uptake may occur through the dopamine transporter [22]
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