Chemistry Reference
In-Depth Information
shows. a. correlation. with. ibril. aggregation. of. α-synuclein.
32
. Another. recently. dis-
covered.mutation.is.E46K.(the.46th.amino.acid.glutamate.is.mutated.to.lysine),.but.
the.effect.of.this.mutation.on.α-synuclein.aggregation.remains.unknown.
33
.While.a.
correlation.between.aggregation.and.α-synuclein.mutations.exists,.the.exact.reason.
for.their.effect.on.the.protein.structure.is.unknown.because.the.effects.on.the.mono-
mer.structure.and.the.mechanism.for.formation.of.the.initial.oligomers,.which.are.
proposed.to.be.pathogenic,.is.unknown.
As. mentioned. earlier,. oxidative. stress. may. play. an. important. role. in. the. devel-
opment. of. Parkinson's. disease.. Several. reactions. in. neuronal. cells. are. capable. of.
producing.ROS,.such.as
16
−
+
−
.
O
→ +
O
2
H
→
H O
→ +
OH OH
→
H O (Mitochondrial respiration)
. (R1)
2
2
2
2
2
Dopamine O
+
2
→
DOPAC NH H O (Dopamine metabolism)
+
+
.
(R2)
.
3
2
2
2
+
−
3
+
H O Fe
+
→ +
OH OH
+
Fe
(Fenton reaction)
.
(R3)
.
2
2
All. of. the. reactions. (R1-R3). produce. ROS. that. are. capable. of. making. oxidative.
modiications. to. proteins.. Experimental. evidence. has. shown. that. oxidative. nitra-
tion.of.α-synuclein.(oxidatively.adding.a.dopamine.adduct).and.peroxide.oxidation.
of. α-synuclein. increase. the. rate. of. aggregation. of. the. protein. into. Lewy. bod-
ies.
4
. Oxidative. stress. is. still. one. of. the. most. prevalent. theories. for. the. etiology. of.
Parkinson's.disease.and.is.also.a.prevailing.theory.in.the.etiology.of.Alzheimer's.dis-
ease,.in.which.α-synuclein.may.also.play.a.role..However,.as.with.the.other.theories.
for.the.causes.of.α-synuclein.aggregation,.the.exact.mechanism.by.which.these.mod-
iications.affect.the.structure-function.relationships.of.α-synuclein.is.still.unclear.
Another. characteristic. feature. in. the. pathogenesis. of. Parkinson's. disease. is.
increased.iron.concentration.in.the.
substantia nigra
.
34
.Iron.concentration.is.typically.
high.in.this.region.of.the.brain,.but.it.has.been.demonstrated.experimentally.that.in.
patients.with.Parkinson's.disease,.the.concentration.is.always.abnormally.high.both.
throughout.the.disease.and.postmortem.
34
.The.exact.reason.for.this.marked.increase.
is.unknown..However,.many.hypotheses.explaining.the.increase.and.its.effect.on.the.
substantia nigra
.are.being.researched.
16
On.average,.the.human.body.contains.3-5.g.of.iron.(this.concentration.is.generally.
lower.in.women).
34
.Iron.is.essential.to.many.processes.in.the.cell,.especially.for.func-
tion.and.development.in.the.brain,.but.iron.concentration.needs.to.be.maintained.at.a.
speciic.level.to.avoid.cytotoxic.reactions.
35
.The.concentration.of.free.iron.in.the.cell.
is. controlled. by. interactions. between. transferrin,. lactoferrin,. divalent. metal. trans-
porter.1.(also.called.DMT1),.ferritin,.and.ferroportin.
35
.Transferrin,.lactoferrin,.and.
DMT1.are.proteins.involved.in.the.import.of.iron.into.cells.
35
.Transferrin.and.lacto-
ferrin.are.iron.carrying.proteins.that.interact.with.receptors.in.the.plasma.membrane.
of.cells.and.import.iron.into.the.cell.through.endocytosis,.whereas.DMT1.is.an.ion.
channel.that.transports.iron.through.the.cell.wall.
35
.Ferritin.is.an.iron.storage.protein.
that.essentially.binds.free.iron.in.the.cell.to.prevent.it.from.participating.in.harmful.
Search WWH ::
Custom Search