Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia

ABSTRACT Abnormalities in subcellular localization and interaction between receptors and their signaling molecules occur within the striatum in Parkinson&s disease (PD) and L‐DOPA‐induced dyskinesia (LID). Synapse‐associated proteins (SAPs), for example, PSD‐95 and SAP97 organize the molecular architecture of synapses and regulate interactions between receptors and downstream‐signaling molecules. Here, we show that expression and subcellular distribution of PSD‐95 and SAP97 are altered in the striatum of unilateral 6‐OHDA‐lesioned rats following repeated vehicle (a model of PD) or L‐DOPA administration (a model of L‐DOPA‐induced dyskinesia). Furthermore, following dopamine‐depletion and development of behavioral deficits in Rotorod performance, indicative of parkinsonism, we observed a dramatic decrease in total striatal levels of PSD‐95 and SAP97 (to 25.6 ± 9.9% and 19.0 ± 5.0% of control, respectively). The remaining proteins were redistributed from the synapse into vesicular compartments. L‐DOPA (6.5mg/kg twice a day, 21 days) induced a rotational response, which became markedly enhanced with repeated treatment (day 1: ‒15.8±7.3 rotations cf day 21: 758.2±114.0 rotations). Post L‐DOPA treatment, PSD‐95 and SAP97 levels increased (367.4 ± 43.2% and 159.9 ± 9.5% from control values, respectively), with both being redistributed toward synaptic membranes from vesicular compartments. In situ hybridization showed that changes in total levels of PSD‐95, but not SAP97, were accompanied by qualitatively similar changes in mRNA. These data highlight the potential role of abnormalities in the subcellular distribution of SAPs in the pathophysiology of a neurological disease.