Structural and Thermodynamic Studies of Synuclein Proteins Related to Parkinson’s Disease: - Metallic Systems: A Quantum Chemist's Perspective - page 34

ROS.production.and.structural.changes.to.the.mitochondria. 26 .The.effects.of.PINK1.
are.just.beginning.to.be.investigated.and.much.research.remains.to.be.done.on.the.
impact.of.this.protein.
A.mutation.in.the.LRRK2.gene.is.the.most.common.autosomal.dominant.muta-
tion.in.familial.Parkinson's.disease. 26 .Very.little.is.known.about.the.function.of.this.
protein.except.that.it.exhibits.some.kinase.activity. 26 .It.has.been.shown.experimen-
tally.that.LRRK2.can.bind.to.the.outer.mitochondrial.membrane,.but.it.has.not.yet.
been.determined.if.it.has.any.effect.on.the.membrane.itself. 26
Mutations. in. the. protein. α-synuclein. are. also. prevalent. in. familial. Parkinson's.
disease..The.common.mutations.of.α-synuclein.that.have.been.shown.to.be.present.
in.brains.affected.by.Parkinson's.disease.are.A53T.(the.53rd.amino.acid.is.changed.
from.alanine.to.threonine).and.A30P.(the.30th.amino.acid.is.changed.from.alanine.
to.proline). 13 .Alpha-synuclein.is.a.140.amino.acid.protein.that.is.extremely.lexible.
and. has. been. shown. experimentally. to. have. a. natively. unfolded. structure. in. solu-
tion. 29 .It.has.further.been.shown.experimentally.that.it.has.some.α-helical.conforma-
tions,.especially.in.the.presence.of.phospholipid.membranes. 29 .Currently,.the.exact.
function.of.α-synuclein.in.the.cell.remains.unknown,.but.it.is.the.main.component.
of. one. of. the. hallmarks. (and,. it. has. been. theorized,. a. pathological. feature). of. the.
disease,. Lewy. bodies. 13 . Lewy. bodies. are. composed. of. a. wide. variety. of. proteins,.
the. most. prevalent. being. α-synuclein,. neuroilaments,. ubiquitin,. and. ubiquinated.
proteins.as.well.as.components.of.the.UPS.pathway. 24 .Recent.studies.have.suggested.
that.iron.is.present.in.Lewy.bodies.as.well,.implying.that.iron.concentration.may.play.
a.role.in.the.aggregation.of.α-synuclein. 24 .Very.little.is.known.about.the.formation.of.
these.inclusions.and.what.effect,.if.any,.that.they.have.on.the.cell.
While.Lewy.bodies.are.a.hallmark.of.Parkinson's.disease,.they.are.just.one.form.
of.a.class.of.protein.inclusions.termed.synucleopathies..Synucleopathies.is.a.general.
term.used.to.refer.to.any.abnormal.aggregation.of.α-synuclein.in.brain.cells.and.they.
are.associated.not.only.with.Parkinson's.disease.but.also.with.Lewy.body.dementia,.
Lewy.body.variant.Alzheimer's.disease,.multiple.system.atrophy,.and.neurodegen-
eration.with.brain.iron.accumulation.type.I. 5,13 .As.a.result.of.many.diseases.being.
linked.to.the.presence.of.synucleopathies,.aggregation.of.α-synuclein.is.theorized.to.
have.a.pathogenic.effect.on.cells.
Alpha-synuclein. has. been. found. experimentally. in. both. small. oligomeric. and.
ilamentous.aggregates. 4 .Experimental.evidence.shows.that.the.ilamental.structures.
may. be. composed. of. oligomeric. structures. and. that. further. aggregation. of. these.
structures.leads.to.the.formation.of.Lewy.bodies. 4 .By.studying.the.mechanism.and.
cause.of.aggregation.of.α-synuclein,.more.can.be.understood.about.the.progression.
of.not.only.Parkinson's.disease,.but.several.other.neurodegenerative.diseases.as.well..
Factors. such. as. concentration,. pH,. ionic. strength,. temperature,. protein. inhibition.
and. stimulation,. lipids,. pesticides,. phosphorylation,. missense. mutations,. oxidative.
stress,. and. the. presence. of. metals. are. proposed. to. affect. α-synuclein. aggrega-
tion. 4,30 .A.triplication.of.the.α-synuclein.gene.is.present.in.one.form.of.autosomal.
dominant. Parkinson's. disease,. which. results. in. a. dramatic. increase. in. the. amount.
of. α-synuclein. present. in. the. cells. 4 . This. dramatic. increase,. inevitably. leading. to.
aggregation. and. development. of. Parkinson's. disease,. shows. that. the. concentration.
of.α-synuclein.is.an.important.factor.to.its.aggregation..This.has.been.shown.both.