Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 32

However,. much. research. needs. to. be. done. in. this. area. to. determine. the. role. this.
might.play.in.the.development.of.Parkinson's.disease.
The. ubiquitin-proteasome. (UPS). pathway. has. also. been. implicated. in. the. pro-
gression.of.Parkinson's.disease..The.UPS.pathway.is.one.of.the.major.pathways.for.
degradation.of.proteins.in.the.cell. 23 .In.general,.a.protein.is.recognized.to.be.ready.
for.destruction.because.it.has.either.reached.the.end.of.its.lifetime.or.is.defective.in.
some.manner.and.the.pathway.is.activated.to.add.ubiquitin.to.the.protein. 23 .Ubiquitin.
acts.as.a.label.on.the.protein.so.that.the.proteasome.system.can.identify,.unfold,.and.
inally. destroy. it. 23 . Malfunction. or. inhibition. of. this. system. causes. the. cell. to. be.
unable.to.degrade.proteins.that.could.potentially.have.a.harmful.effect.
Several. theories. have. been. suggested. for. errors. in. the. UPS. pathway. and. their.
effect. on. the. brain.. Postmortem. examination. of. brains. of. Parkinson's. disease.
patients. has. shown. that. proteasome. activity. is. signiicantly. decreased,. and. recent.
evidence.has.linked.several.of.the.mutations.associated.with.Parkinson's.disease.to.
the.UPS.pathway. 24 .One.of.the.most.signiicant.links.between.the.UPS.pathway.and.
Parkinson's. disease. is. the. protein. parkin,. which. is. one. of. several. ubiquitin. ligase.
(E3).proteins. 23 .E3.proteins.transfer.ubiquitin.from.an.ubiquitin-conjugating.enzyme.
(E2).protein,.which.accepts.the.ubiquitin.from.an.ubiquitin.activating.protein.(E1),.to.
the.protein.that.is.going.to.be.degraded. 23 .E3.proteins.are.vital.to.the.UPS.pathway.
because.they.not.only.recognize.the.proteins.that.need.to.be.degraded.but.also.trans-
fer.the.marker.for.degradation.to.that.protein. 23 .An.autosomal.recessive.(both.genes.
must.be.mutated.in.order.for.the.effect.to.be.observed).mutation.in.parkin.is.found.
in.over.50%.of.people.with.juvenile.and.early.onset.parkinsonism. 25 .Interestingly,.
α-synuclein.and.synphilin-1.have.been.identiied.as.proteins.that.parkin.is.respon-
sible.for.targeting.for.degradation.and.these.proteins.are.also.the.main.components,.
along.with.ubiquitin,.of.Lewy.bodies. 23
Mutations.in.ubiquitin.C-terminal.hydrolase.L1.(UCH-L1).have.also.been.associ-
ated.with.interfering.in.the.UPS.pathway.in.an.autosomal.dominant.(only.one.gene.
must.be.mutated.for.the.effect.to.be.observed).form.of.hereditary.Parkinson's.dis-
ease. 24 .UCH-L1.is.another.key.enzyme.in.the.UPS.pathway.and.the.mutation.of.this.
enzyme.was.discovered.in.a.rare.case.of.familial.Parkinson's.disease. 24 .The.actual.
function.of.this.enzyme.remains.unknown,.so.the.effect.of.this.mutation.on.the.cell.
is. still. undetermined. 24 . Like. many. topics. in. Parkinson's. disease,. further. research.
is.needed.to.better.understand.how.this.mutation.may.cause.the.devastating.effects.
associated.with.this.disease.
While.parkin.and.UCH-L1.mutations.are.associated.with.hereditary.Parkinson's.
disease,.this.accounts.for.less.than.10%.of.those.affected..Environmental.factors,.such.
as.dopaminergic.neurotoxins,.have.also.been.shown.to.produce.effects.on.the.UPS.
system. 17 .Compounds.such.as.1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine.(MPTP),.
rotenone,.paraquat,.dopamine,.6-hydroxydopamine.(6-OHDA),.iron,.manganese,.and.
dieldrin.have.all.shown.evidence.of.affecting.the.UPS.pathway.either.directly.or.by.
causing.other.effects.in.the.cell,.such.as.oxidative.stress.and.protein.aggregation. 25 .
This. strengthens. the. theory. that. it. is. actually. a. combination. of. intracellular. events.
that.results.in.the.dopaminergic.cell.death.associated.with.Parkinson's.disease.
Oxidative.stress.is.another.prominent.hypothesis.in.the.development.of.Parkinson's.
disease. 21 .Oxidative.stress.results.when.the.cell.produces.or.is.exposed.to.more.free.