Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 31

to.dopaminergic.neuronal.cell.death.in.the. substantia nigra .that.occurs.as.a.result.of.
Parkinson's.disease.
The. substantia nigra . is. a. compact. collection. of. mostly. dopaminergic. neurons.
located.in.the.mid.brain.and.appears.to.control.motor.function.throughout.the.body. 19 .
This.region.of.the.brain.is.easily.characterized.by.its.dark.color,.which.is.also.the.
origin.of.the.name. substantia nigra .(from.the.Latin.meaning.black.body),.relative.
to. the. surrounding. neurons. due. to. the. presence. of. a. pigment. called. neuromelanin.
in.the.cells. 19 .Currently,.no.active.neuromelanin.synthesis.pathway.is.known,.but.it.
is.hypothesized.to.be.a.by-product.of.the.autoxidation.of.dopamine.and.noradrena-
line.in.neuronal.cells,.which,.until.recently,.was.assumed.to.be.inert. 19 .One.recent.
hypothesis.is.that.the.neuromelanin,.like.peripheral.melanins.in.cells.outside.of.the.
central. nervous. system,. serves. a. protective. role. in. dopaminergic. neuronal. cells. 22 .
Peripheral.melanins.protect.cells.from.free.radical.damage.by.inactivating.them. 22 .
It.is.hypothesized.that.neuromelanin.may.protect.the.cell.from.toxic.by-products.of.
dopamine.metabolism.and.oxidation.and.may.also.play.a.role.in.maintaining.iron.
homeostatis.in.the.neuronal.cells. 22
Experimental.evidence.shows.that.as.the.dopaminergic.cells.degenerate.during.
the.progression.of.Parkinson's.disease,.the.dying.cells.release.stored.neuromelanin,.
causing.a.marked.decrease.in.the.pigmentation.of.the. substantia nigra . 19 .Although.
these. are. not. the. only. cells. affected. by. Parkinson's. disease,. the. decrease. in. dark.
color.of.the. substantia nigra .of.the.brain.is.one.of.the.pathological.diagnostic.criteria.
for.this.disease. 19 .Some.studies.suggest.that.this.pattern.of.discoloration.is.not.ran-
dom.and.that.neuromelanin.may.play.a.role.in.the.pathogenesis..However,.whether.
the.discoloration.has.a.positive.or.negative.effect.on.the.cell.is.still.debated. 19 .One.
theory.suggests.that.the.presence.of.neuromelanin.may.have.a.negative.inluence.on.
neuronal.cells.since.the.pathway.from.which.neuromelanin.is.believed.to.be.synthe-
sized.also.produces.other.active.oxidizers.such.as.quinine,.semiquinone,.and.super-
oxide. radicals. 19 . Therefore,. increased. neuromelanin. would. indicate. an. increased.
amount.of.oxidizers.present.in.the.cell,.which.could.lead.to.cell.damage.in.a.variety.
of.ways..Another.theory.suggests.that.neuromelanin.may.in.fact.have.a.positive.inlu-
ence. on. cells. during. the. progression. of. Parkinson's. disease. 19 . This. theory. comes.
from.an.observation.by.Gibb.that. substantia nigra .neuronal.cells.that.contain.less.
neuromelanin.are.more.susceptible.to.degeneration,.i.e.,.they.are.the.irst.to.die,.in.
Parkinson's.disease.than.cells.that.are.more.heavily.pigmented.by.neuromelanin. 19 .
Additionally,.there.is.some.evidence.that.the.structure.of.neuromelanin.in.the.par-
kinsonian.brain.may.differ.from.a.healthy.brain.or.that.parkinsonian.brain.neurons.
may.contain.less.neuromelanin.than.healthy.neurons. 19 .Despite.these.studies,.the.role.
of.neuromelanin.in.the.brain.still.remains.unclear.
Experimental.evidence.shows.that.neuromelanin.is.capable.of.binding.a.variety.
of.metal.ions,.including.iron,.copper,.zinc,.and.lead..In.addition,.the. substantia nigra .
contains.several.metal.ions,.including.iron,.at.concentrations.up.to.four.times.that.
of.other.neuronal.cells. 19,22 .There.is.some.experimental.evidence.of.iron.binding.to.
neuromelanin,.but.the.actual.role.of.this.binding.remains.unclear. 19,22 .It.is.hypoth-
esized.that.neuromelanin.may.have.a.function.similar.to.the.protein.ferritin,.which.is.
to.store.iron.in.the.cell.in.an.effectively.chemically.inactive.state.until.it.is.needed. 22 .