accepted manuscript

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high lipophilicity and is oxidized to a pyridinium species by monoamine oxidase
(MAO) B in glial cells [25, 26]. This species is further oxidized to the toxic molecule
MPP + , which is released by an unknown mechanism and can be taken up into
dopaminergic neurons via the dopamine transporter [27]. Within neurons MPP + is
concentrated in mitochondria and inhibits complex I (NADH:ubiquinone
oxidoreductase) of the electron transport chain [28, 29]. As a consequence of
impaired electron flux through complex I, mitochondrial ATP production is decreased
while the generation of reactive oxygen and nitrogen species is increased [30-36]. The
downstream events leading ultimately to neuronal cell death seem to be complex and
involve activation of pro-apoptotic Bcl-2 family members, p53, JNK, and caspases as
well as inflammation [18, 37-43].
Insights into the molecular actions of MPTP brought up the question whether
complex I activities might be impaired in patients suffering from sporadic PD. Indeed,
complex I activities were reported to be significantly reduced (in the range of 30%) in
post-mortem substantia nigra of PD patients [44-47], and platelets from PD patients
[48-51], while data from skeletal muscle and other non-neuronal tissues are not
consistent [52-56]. Although the complex I deficiency was first reported to be specific
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for the substantia nigra [57], a 30% reduction in complex I activity was recently
detected also in frontal cortex mitochondria from PD postmortem brain [58, 59].
Interestingly, Keeney et al. could demonstrate that catalytic subunits of complex I
derived from PD frontal cortex mitochondria are oxidatively damaged, correlating
with complex I misassembly and dysfunction [59]. Whether this increase in oxidative
damage is specific for complex I and which subunits are affected has not been
addressed so far.
In conclusion, several lines of evidence substantiated a link between PD and
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