G209A mutant alpha synuclein expression specifically enhances dopamine induced oxidative damage.
Alpha synuclein protein may play an important role in familial and sporadic Parkinson's disease pathology. We have induced G209A mutant or wild-type alpha-synuclein expression in stable HEK293 cell models to determine if this influences markers of oxidative stress and damage under normal conditions or in the presence of dopamine or paraquat. Induced wild-type or mutant alpha-synuclein expression alone had no effect upon levels of oxidative stress or damage, as measured by glutathione levels or aconitase activity. Both wild-type and mutant alpha-synuclein expression decreased the oxidative damage induced by paraquat, although the protection was less marked with mutant alpha-synuclein expression. This suggests that alpha-synuclein expression may either have anti-oxidant properties or may upregulate cellular antioxidant levels, a function that was diminished by the G209A mutation. However, mutant but not wild-type alpha-synuclein expression specifically enhanced dopamine associated oxidative damage. Non-expressing cells treated with reserpine to inhibit the vesicular monoamine compartmentalisation produced similar results. However, consistent with the hypothesis that mutant alpha-synuclein disrupts vesicular dopamine compartmentalization, this effect was diminished in cells expressing mutant alpha-synuclein. This may result in increased dopamine metabolism and cause selective oxidative damage to dopaminergic cells.
Orth
M
M
University Department of Clinical Neurosciences, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK.
Tabrizi
S J
SJ
Tomlinson
C
C
Messmer
K
K
Korlipara
L V P
LV
Schapira
A H V
AH
Cooper
J M
JM
D000154:Aconitate Hydratase / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D010269:Paraquat / Q000633:toxicity; D012110:Reserpine / Q000494:pharmacology; D051843:Synucleins; D051844:alpha-Synuclein
D018759:Adrenergic Uptake Inhibitors; D006540:Herbicides; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D004441:Ecdysterone; C008999:ponasterone A; D012110:Reserpine; D000154:Aconitate Hydratase; D005978:Glutathione; D010269:Paraquat; D004298:Dopamine