Adenosine A1 Receptor Ligands Bind to α-Synuclein: Implications for α-Synuclein Misfolding and α-Synucleinopathy in Parkinson’s Disease

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Abstract Background:Accumulating α-synuclein (α-Syn) aggregates in neurons and glial cells are the staples of many synucleinopathy disorders, such as Parkinson’s disease. Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor (A1R) stimulation leads to neurodegeneration, we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promote α-Syn aggregation (e.g., the amphetamine analogue 2-aminoindan) or inhibit α-Syn aggregation (e.g., Rasagiline metabolite 1-aminoindan). In the present study, we determined whether adenosine, the A1R receptor agonist N6-Cyclopentyladenosine (CPA) and antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) directly interact with α-Syn to modulate α-Syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra (SN). Methods:Nanopore analysis and molecular dynamics simulation were used to test the binding properties of CPA and DPCPX with α-Syn in vitro. Sprague-Dawley rats were administered 7-day intraperitoneal injections of the A1R ligands and 1- and 2-aminoindan, and levels of α-Syn aggregation and neurodegeneration were examined in the substantia nigra pars compacta region. Results:Using nanopore analysis, we showed that the A1R agonists (CPA and adenosine) interacted with the N-terminus of α-Syn, similar to 2-aminoindan, which is expected to promote a “knot” conformation and α-Syn misfolding. In contrast, the A1R antagonist DPCPX interacted with the N- and C-termini of α-Syn, similar to 1-aminoindan, which is expected to promote a “loop” conformation which prevents α-Syn misfolding. Molecular docking studies revealed that adenosine, CPA and 2-aminoindan interacted with the hydrophobic core of α-Syn N-terminus, whereas DPCPX and 1-aminoindan showed direct binding to the N- and C-terminal hydrophobic pockets. Histological and confocal imaging studies revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increased α-Syn aggregation and neurodegeneration in SN pars compacta. In contrast, DPCPX and 1-aminoindan attenuated CPA-induced neurodegeneration but did not significantly reduce α-Syn aggregation.Conclusions:The results indicate A1R agonists and drugs promoting a “knot” conformation of α-Syn can cause α-synucleinopathy and increase neuronal degeneration, whereas A1R antagonists and drugs promoting a “loop” conformation of α-Syn can be harnessed for possible neuroprotective therapies to decrease α-synucleinopathy in Parkinson’s disease.

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