accepted manuscript

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1. Sporadic PD and mitochondria
1.1. Complex I deficiency
1.1.1. Lessons from an illicit drug
In the late 1970s/early 1980s young drug addicts in the US developed
progressive and irreversible parkinsonism after using an illicit drug intravenously.
The neurotoxic compound was traced back to MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine), a by-product generated accidentally during the synthesis of a
meperidine analog [11, 12]. One of these patients, a chemistry graduate student who
died of a drug overdose two years after the onset of parkinsonian symptoms,
displayed degeneration of the substantia nigra pars compacta without a clear evidence
for the presence of Lewy bodies [12]. These findings were confirmed when three
more patients came to autopsy 3 to 16 years after MPTP intoxication [13]. A PD-
specific pattern of nigrostriatal degeneration without typical Lewy body pathology
has also been observed in non-human primates treated with MPTP [14-17].
Importantly, both the beneficial and longterm adverse effects of L-dopa therapy in
MPTP-intoxicated patients/non-human primates are comparable to those in patients
suffering from sporadic PD. The neuropathological and clinical similarities between
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MPTP-induced parkinsonism and sporadic PD promoted the employment of the
MPTP monkey model for neuropathological, neurophysiological and preclinical
therapeutical studies (rev. in [18]). For reasons of practicability, the MPTP model has
also been established in mice, which is now widely used to study some aspects of PD
(see [18-24] for detailed reviews on PD animal models).
In parallel to neuropathological studies in MPTP-treated animals, considerable
efforts have been made to understand the molecular mechanism of MPTP-induced
neurotoxicity. It turned out that MPTP crosses the blood brain barrier by virtue of its
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