Chemistry Reference
In-Depth Information
radicals. or. reactive. oxygen. species. (ROS). than. it. can. neutralize. before. the. ROS.
causes.damage.to.either.the.DNA,.proteins,.or.lipids. 21 .ROS.such.as. O H,. O 2 ,.N O ,.
and.H 2 O 2 .can.cause.DNA.mutation.and.breakage,.protein.mutation.and.mis-folding,.
and.membrane.damage.by.reacting.with.lipids. 26 .There.are.a.variety.of.ways.that.ROS.
can.be.produced.in.the.cell..One.of.the.most.common.and.well-known.methods.is.the.
Fenton.reaction,.which.converts.hydrogen.peroxide.(H 2 O 2 ).in.the.presence.of.Fe 2+ .to.
form.OH ,.and. O H.(the.hydroxyl.radical).and.oxidizes.Fe 2+ .to.Fe 3+ . 7 .If.excess.iron.is.
present.in.the.cell,.as.is.the.case.with.Parkinson's.disease,.it.can.produce.excess.ROS,.
which,.left.unchecked,.will.produce.extensive.damage.throughout.the.cell.
While.Parkinson's.disease.symptoms.are.typically.a.result.of.a.lack.of.dopamine-
producing.neurons,.dopamine.itself.can.also.cause.oxidative.stress.in.cells..Dopamine.
is.degraded.by.either.monoamine.oxidase.A.or.autoxidation. 21 .When.dopamine.under-
goes.autoxidation,.it.increases.the.amount.of.ROS.and.precursors.to.ROS..Coupled.with.
the.increase.in.nigral.iron,.this.can.have.a.devastating.effect.on.the.cell..Postmortem.
analysis.of.parkinsonian.brains.has.shown.that.damage.from.oxidative.stress.is.preva-
lent.throughout.all.of.the.neuronal.tissue,.not.only.the. substantia nigra . 21
Exposure.to.some.pesticides,.herbicides,.and.industrial.chemicals.are.also.poten-
tial. risk. factors. for. Parkinson's. disease. primarily. due. to. their. ability. to. increase.
oxidative.stress.in.neuronal.cells..One.prominent.example.of.this.is.MPTP,.which.is.
a.toxic.by-product.of.the.production.of.an.opioid.similar.to.meperidine. 17 .The.effects.
of.MPTP.were.discovered.when.a.contaminated.opioid.was.injected.by.drug.users.
who.subsequently.developed.symptoms.of.Parkinson's.disease. 17 .MPTP.is.converted.
into. 1-methyl-4-phenylpyridinium. (MPP+),. a. pyridinium. ion,. by. monoamine. oxi-
dase.B.in.the.glial.cells.(non-neuronal.brain.cells). 18,26 .After.MPP+.is.taken.up.into.
the.dopaminergic.cells.via.the.dopamine.transporter,.it.interferes.with.mitochondrial.
respiration.by.inhibiting.complex.I,.which.causes.a.decrease.in.mitochondrial.ATP.
production.and.an.increase.in.ROS. 18,26
Inhibition.of.complex.I.is.a.common.theme.in.another.hypothesis.of.the.develop-
ment.of.Parkinson's.disease,.mitochondrial.dysfunction. 17 .Complex.I.is.the.enzyme.
that. catalyzes. the. transfer. of. electrons. from. nicotinamide. adenine. dinucleotide.
(NADH).to.ubiquinone.in.the.irst.step.in.the.electron.transport.chain.in.mitochon-
dria. 26 .Mitochondrial.dysfunction.causes.an.increase.in.ROS.since.that.is.where.the.
majority. of. them. are. formed.. A. variety. of. chemicals. and. mutations. can. result. in.
mitochondrial.dysfunction.
Genetic.mutations.are.also.commonly.observed.in.the.study.of.Parkinson's.dis-
ease. 27 .By.studying.the.known.genetic.mutations.that.result.in.Parkinson's.disease,.
it. is. possible. that. an. understanding. of. the. mechanism. that. results. in. the. clinical.
symptoms.will.be.determined.and.assist.in.identifying.the.cause.of.idiopathic.forms.
of.Parkinson's.disease..A.variety.of.genetic.mutations.are.discussed.in.the.following.
that.are.linked.to.Parkinson's.disease.
A.mutation.in.the.gene.PINK1.causes.an.autosomal.recessive.form.of.early.onset.
parkinsonism.by.decreasing.the.function.of.PINK1. 26,28 .The.exact.function.of.PINK1.
in.the.cell.is.unknown,.but.the.effects.of.the.mutation.on.the.function.of.mitochon-
dria.are.far.reaching. 26 .Decreased.PINK1.results.in.a.decrease.in.the.mitochondrial.
membrane. potential,. inhibition. of. complex. I. and. IV. activity. in. the. electron. trans-
port. chain,. a. decrease. in. adenosine. triphosphate. (ATP). production,. an. increase. in.
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