In article <E28C1o.Aqo at murdoch.acc.Virginia.EDU>,
dsc9w at avery.med.Virginia.EDU (David Cassarino) wrote:
> There is loads of evidence that the vast majority of
> Parkinson's disease (PD) is genetic.
> Autosomal dominant forms of PD have been demonstrated, but the
> inheritance of most cases looks "sporadic". Recent evidence
> has shown that these cases can often be interpreted as actually being
> maternal (ie, mitochondrial).
Often times, there is no gender skewness with respect to susceptibility to
PD. Only a few studies have shown that. Most also cite that caucasians
are more susceptible to PD than are blacks and asians.
> Mitochondrial defects in the electron transport chain protein
> complex I have long been known to characterize PD (Parker et
> al), and these defects are systemic, not just in the
> dopaminergic (DA) cells of the substantia
> nigra (SN, the locus for degeneration in PD), consistent with
> inheritance (but also with a toxin etiology).
>> Significantly, mitochondrial DNA (mtDNA)deletions and point mutations
> have been demonstrated to be associated with PD (see papers by Ikebe,et al)
> and it also is known that the complex I defect transfers
> with mtDNA(Swerdlow et al), confirming its genetic etiology.
>> These mutations are thought to impair electron transport,
> inhibiting ATP production, and generating free radicals, both
> of which may be toxic to the cells. The reason the SN
> selectively dies in PD is most likely due to the high
> concentrations of Fe and neuromelanin (not melatonin!) in the
> SN, both of which generate free radicals, as does the oxidative
> metabolism of DA itself. Free radical markers of damage to
> proteins, lipids and DNA (nitrotyrosine, lipid peroxides,
> and deoxyguanosine, res.) are increased in PD tissues (again,
> not just brain). These effects ultimately lead to cell death,
> probably through the apoptotic cascade.
>This is still speculative. Neuromelanin and its associated standing free
radical may actually protect DA neurons. Metal chelation is probably a
side advantage (except for the Fe+3 <-> +2 cycling). Remember how
neuromelanin is formed: from dopaquinones, cysteine/glutathione
conjugated or not. Dopamine just so happens to autooxidize and produce
various quinone derivatives which can act either as redox cyclers or
alkylating agents. Neuromelanin is thought to actually be a sink for
these damaging species.
As far as apoptosis, this sounds like a really good explanation and would
be a logical conclusion if it were true. This was my first assumption
when I began plowing through the literature four years ago, but there
really is NO evidence of apoptosis in parkinsonian post mortems.
Apoptosis is only found in 6-hydroxydopamine or MPTP lesioned rodent brain
or DA cell cultures.
> No. The mechanism of MPTP is well established--it's active
> metabolite, MPP+ (produced in astrocytes NOT in "melatonin cells"
> --which exist only in the pineal gland--diffuses into the
> surrounding intercellular space and is uptaken by all cells,
All cells? The basis for selectivity is a higher affinity for the DA
transporter, although there is some binding to 5-HT and adrenergic
> but selectively concentrated in DA-neurons via the DA reuptake
> transporter) inhibits complex I of the ETC--causing free
> radical production, etc.
And ATP depletion. However, neurons are capable of sustaining the
transmembrane potential with glycolytic ATP alone for limited periods of
time (see recent research by Erecinska or Chance). The idea that MPP+
acts as a complex I inhibitor is not necessarily taken as the end-all
answer by many neuroscientists. Do you know what the Ki for inhibition of
oxygen consumption by MPP+ is? Its 160 micromolar, not very potent.
That's a hell of lot of MPP+ you'd have to pack in there, mitochondrial
electrical gradient or not. Really, drugs that you have to use more than
100 micromolar to get an appreciable effect are not really very potent
drugs. For MPP+, the spread is only two orders of magnitude so even a
small effect on respiration would be cause by concentrations near IC20
(about 80 micromolar, or 1/2 the Ki).
It also probably messes up calcium
> buffering too, which may contribute to apoptosis (see the
> Swerdlow paper).
Most neurons have calcium levels slightly below optimum for cell stability
(probably works as a buffering range). Increasing calcium in a neuron
actually stabilizes it. Only under extreme calcium loading (>15 mM; see
Eimerl & Schramm and more recent works) which overrides the ability to
buffer with calcium binding proteins and sequester to ER storage does
calcium induce apoptosis. Mitochondria are surprisingly tough when it
comes to calcium loading as they routinely interrupt respiration briefly
to buffer cyctosolic calcium and release sodium. Although I agree that
the neurodegenerative mechanism is probably induction of some pathway
which leads to instability or reduced responsiveness to trophic factors,
to date there really is NO evidence to support apoptosis as a mechanism in
idiopathic Parkinson's disease.
> BTW, the nigral cells are black because one of the products of
> DA-metabolism is melanin (not melatonin, but the same stuff in
> melanocytes, the pigmented cells in your skin which give rise
> to moles and melanomas), which accumulates in
> the nigra with aging and is thought to contribute to its
> degeneration via enhanced free-radical gereration.
mkirby at vt.edu