Chemistry Reference
In-Depth Information
in.laboratory.experiments.and.in.the.brain..Changes.in.pH,.ionic.strength,.and.tem-
perature. can. also. affect. the. rate. of. aggregation. of. α-synuclein.
4
. The. aggregation.
of. α-synuclein. has. been. observed. experimentally. under. varying. conditions. of. pH.
and.ionic.strength.
4,31
.These.experiments.demonstrated.that.as.the.pH.decreases,.the.
rate. of. aggregation. increases. and. that. with. increasing. ionic. strength. the. aggrega-
tion.rate.increases.
4,31
.Increasing.ionic.strength.also.causes.the.aggregate.to.take.a.
more.amorphous.shape.compared.to.the.cross-β.conformation.normally.observed.
4
.
Temperature.has.also.been.shown.to.increase.the.rate.of.aggregation.of.α-synuclein.
and. as. with.ionic.strength. the. conformation. of. the. ilaments. produced. is. different.
from.the.conformation.at.physiological.temperature.
4
Several.proteins.are.also.capable.of.inhibiting.or.stimulating.α-synuclein.aggre-
gation.. Both. β-. and. γ-synuclein. are. homologues,. meaning. that. they. contain. the.
same.sequences,.but.may.be.shorter.or.longer.and.perform.similar.functions.com-
pared. to. α-synuclein.. Interestingly,. they. both. have. been. shown. to. inhibit. in. vitro.
α-synuclein. aggregation.
4
. On. the. other. hand,. proteins. such. as. tau,. histones,. and.
brain-speciic. protein. p25α. have. all. been. shown. to. increase. the. in. vitro. aggrega-
tion. rate. of. α-synuclein.
4
. Tau. proteins. stabilize. microtubules. by. interacting. with.
tubulin.in.central.nervous.system.neurons.and.defects.in.tau.proteins.are.generally.
associated.with.Alzheimer's.disease..However,.tau.is.also.a.component.of.Lewy.bod-
ies.
4
.Brain-speciic.protein.p25α.is.a.tubulin.polymerization.promoting.protein.that.
has.been.shown.to.be.a.component.of.Lewy.bodies.
4
.Histones.are.proteins.that.are.
responsible.for.ordering.DNA.in.the.nucleus.of.eukaryotic.cells.
4
.It.has.been.shown.
experimentally.that.histones.and.α-synuclein.often.associate.in.the.presence.of.toxic.
species;.however,.histones.have.not.been.observed.in.Lewy.bodies.
4
.The.mechanism.
by.which.these.proteins.interact.with.and.affect.α-synuclein.still.remains.unknown,.
but.there.are.theories.that.suggest.that.the.process.occurs.through.ionic.interactions.
Lipids. and. pesticides. can. also. increase. the. rate. of. aggregation. of. α-synuclein.
4
.
Experimental.evidence.has.already.shown.that.in.the.presence.of.lipids,.the.confor-
mation.of.α-synuclein.changes.from.its.normally.unstructured.form.to.an.α-helical.
structure.
2,29
.Additionally,.α-synuclein.has.been.shown.to.ibrilize.and.form.amor-
phous. aggregates. in. the. presence. of. fatty. acids.
4
. The. mechanism. that. causes. this.
increase. in. aggregation. remains. largely. unknown.. As. discussed. previously. in. the.
chapter,.exposure.to.pesticides.such.as.paraquat.can.cause.a.temporary.aggregation.
of.α-synuclein.resulting.in.Parkinson's.disease.symptoms,
25
.but.again,.the.mecha-
nism.through.which.it.increases.aggregation.remains.unclear.
Phosphorylation. of. proteins. can. also. greatly. affect. their. structure.. Under. nor-
mal. in. vivo. conditions,. α-synuclein. primarily. remains. unphosphorylated.
4
. Upon.
examination.of.the.protein.isolated.from.synucleopathies,.α-synuclein.shows.phos-
phorylation. at. the. 129th. amino. acid. (serine).
4
. These. results. have. been. reproduced.
in. transgenic. mice.as. well. as. in. vitro.
4
. Additional. in. vitro. experiments. have. dem-
onstrated.that.phosphorylated.α-synuclein.forms.aggregates.at.a.faster.rate.than.the.
wild-type.α-synuclein.
4
.The.actual.effect.that.this.phosphorylation.has.on.the.mono-
mer.structure.remains.unknown.and.is.one.of.the.topics.under.study.in.our.group.
Missense. mutations,. such. as. A53T. and. A30P,. have. been. shown. to. accelerate.
α-synuclein.aggregation,.but.in.different.manners.
4,32
.The.A30P.mutation.shows.a.cor-
relation.with.the.oligomeric.aggregation.of.α-synuclein,.whereas.the.A53T.mutation.
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