Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia.
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.
Nash
J E
JE
Toronto Western Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada. jnash@uhnres.utoronto.ca
Johnston
T H
TH
Collingridge
G L
GL
Garner
C C
CC
Brotchie
J M
JM
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis* / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000648:ultrastructure; D001923:Brain Chemistry; D002462:Cell Membrane / Q000737:chemistry; D003342:Corpus Striatum / Q000737:chemistry / Q000648:ultrastructure; D000074288:Discs Large Homolog 1 Protein; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D020820:Dyskinesias / Q000209:etiology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis* / Q000235:genetics; D007980:Levodopa; D008297:Male; D008565:Membrane Proteins / Q000032:analysis* / Q000235:genetics; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000737:chemistry*; D013569:Synapses / Q000737:chemistry*
D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; C501444:DLG4 protein, human; D000074288:Discs Large Homolog 1 Protein; D000076122:Disks Large Homolog 4 Protein; C501119:Dlg1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D007980:Levodopa; D016627:Oxidopamine