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Proteome analysis of soluble nuclear proteins reveals that HMGB1/2
suppress genotoxic stress in polyglutamine diseases.Qi ML, Tagawa K, Enokido Y, Yoshimura N, Wada Y, Watase K, Ishiura S, Kanazawa
I, Botas J, Saitoe M, Wanker EE, Okazawa HNat Cell Biol2007 Apr 9(4):402-14 [abstract on PubMed] [citations on Google
Scholar] [related articles] [full text] [order article]
Selected by | Leslie ThompsonEvaluated 30 Apr 2007Browse relevant Sections
View additional info
FacultyComments
Faculty Comments
Faculty Member
This study
shows thatimportant
nuclear
regulatoryproteins -
HMGB1/2 -are altered in
polyglutamine
disease andthat their
upregulation
can reversegeneraltranscriptiona
l repressionand reduces
genotoxicstress
induced byexpression of
mutant ataxinand
huntingtin.
This articlereports thenovel finding
that theubiquitous
and abundantnon-histone
chromosomal
proteins(HMGB1/2),
which are key
http://www.f1000medicine.com/pubmed/17384639http://www.f1000medicine.com/pubmed/gs/17384639http://www.f1000medicine.com/pubmed/gs/17384639http://www.f1000medicine.com/related/17384639http://www.f1000medicine.com/fulltext/doi/10.1038/ncb1553http://www.f1000medicine.com/fulltext/order/17384639http://www.f1000medicine.com/article/id/1080773/evaluation/sectionshttp://www.f1000medicine.com/article/id/1080773/evaluation/additionalhttp://www.f1000medicine.com/pubmed/gs/17384639http://www.f1000medicine.com/pubmed/gs/17384639http://www.f1000medicine.com/related/17384639http://www.f1000medicine.com/fulltext/doi/10.1038/ncb1553http://www.f1000medicine.com/fulltext/order/17384639http://www.f1000medicine.com/article/id/1080773/evaluation/sectionshttp://www.f1000medicine.com/article/id/1080773/evaluation/additionalhttp://www.f1000medicine.com/pubmed/173846398/8/2019 PolyQ From f1000 Medcine
2/47
regulators of
geneexpression
and DNAintegrity,
show reducedsoluble levels
in models ofboth
Huntington'sdisease (HD)
andspinocerebella
r ataxia type1(SCA1).
Increasedexpression of
these HMGBproteins is
protective in
primaryneurons andDrosophila
polyglutamine
models.Results from
otherlaboratories
have
implicatedaltered
nuclear
functions andtranscriptional alterations
inpolyglutamine
disease. Thisstudy
provides anovel
approach forintervention
in HD andSCA1 and
suggests anew function
for HMGB1/2in
polyglutaminepathology.
Competing
interests: No
8/8/2019 PolyQ From f1000 Medcine
3/47
potential
interestsrelevant to
this articlewere
reported.Evaluated 30
Apr 2007
LeslieThompson
University ofCalifornia Irvine,
United States ofAmerica
NEUROLOGICALDISORDERS
New Finding
Faculty Member
This study
shows thatimportant
nuclearregulatory
proteins -HMGB1/2 -
are altered in
polyglutaminedisease andthat their
upregulationcan reverse
generaltranscriptiona
l repressionand reduces
genotoxic
stressinduced by
expression of
mutant ataxinand
huntingtin.This article
reports thenovel finding
that theubiquitous
and abundantnon-histone
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/14508239563611368/8/2019 PolyQ From f1000 Medcine
4/47
chromosomal
proteins(HMGB1/2),
which are keyregulators of
geneexpression
and DNAintegrity,
show reducedsoluble levels
in models ofboth
Huntington'sdisease (HD)
andspinocerebella
r ataxia type1(SCA1).
Increased
expression ofthese HMGBproteins is
protective in
primaryneurons and
Drosophilapolyglutamine
models.
Results fromother
laboratories
haveimplicatedaltered
nuclearfunctions and
transcriptional alterations
inpolyglutamine
disease. Thisstudy
provides anovel
approach forintervention
in HD andSCA1 and
suggests anew function
for HMGB1/2
inpolyglutamine
pathology.
8/8/2019 PolyQ From f1000 Medcine
5/47
Competing
interests: Nopotential
interestsrelevant to
this articlewere
reported.Evaluated 30
Apr 2007
LeslieThompson
University ofCalifornia Irvine,
United States ofAmerica
NEUROLOGICAL
DISORDERS
New Finding
Faculty Member
This study
shows thatimportant
nuclear
regulatoryproteins -HMGB1/2 -
are altered inpolyglutamine
disease andthat their
upregulationcan reverse
general
transcriptional repression
and reduces
genotoxicstress
induced byexpression of
mutant ataxinand
huntingtin.This article
reports thenovel finding
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/14508239563611368/8/2019 PolyQ From f1000 Medcine
6/47
that the
ubiquitousand abundant
non-histonechromosomal
proteins(HMGB1/2),
which are keyregulators of
geneexpression
and DNAintegrity,
show reducedsoluble levels
in models ofboth
Huntington'sdisease (HD)
and
spinocerebellar ataxia type1(SCA1).
Increased
expression ofthese HMGB
proteins isprotective in
primary
neurons andDrosophila
polyglutamine
models.Results fromother
laboratorieshave
implicatedaltered
nuclearfunctions and
transcriptional alterations
inpolyglutamine
disease. Thisstudy
provides anovel
approach forintervention
in HD and
SCA1 andsuggests a
new function
8/8/2019 PolyQ From f1000 Medcine
7/47
for HMGB1/2
inpolyglutamine
pathology.
Competing
interests: Nopotential
interestsrelevant to
this articlewere
reported.Evaluated 30
Apr 2007
LeslieThompson
University of
California Irvine,United States ofAmerica
NEUROLOGICAL
DISORDERS
New Finding
Faculty MemberComments
This studyshows thatimportant
nuclearregulatory
proteins -HMGB1/2 - are
altered inpolyglutamine
disease and
that theirupregulation
can reverse
generaltranscriptional
repression andreduces
genotoxic stressinduced by
expression ofmutant ataxin
and huntingtin.This article
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/14508239563611368/8/2019 PolyQ From f1000 Medcine
8/47
reports the
novel findingthat the
ubiquitous andabundant non-
histonechromosomal
proteins(HMGB1/2),
which are keyregulators of
gene expressionand DNA
integrity, showreduced soluble
levels in modelsof both
Huntington'sdisease (HD)
and
spinocerebellarataxia type1(SCA1).
Increased
expression ofthese HMGB
proteins isprotective in
primary
neurons andDrosophila
polyglutamine
models. Resultsfrom otherlaboratories
have implicatedaltered nuclear
functions andtranscriptional
alterations inpolyglutamine
disease. Thisstudy provides
a novelapproach for
intervention inHD and SCA1
and suggests anew function for
HMGB1/2 inpolyglutamine
pathology.
Competing
8/8/2019 PolyQ From f1000 Medcine
9/47
interests: No
potentialinterests
relevant to thisarticle were
reported.Evaluated 30
Apr 2007
Leslie ThompsonUniversity of California Irvine, United
States of AmericaNEUROLOGICAL DISORDERS
New Finding
The first 17 amino acids of Huntingtin modulate its sub-cellular
localization, aggregation and effects on calcium homeostasis.
Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, SullivanPG, Steffan JS, Sensi SL, Thompson LM
Hum Mol Genet2007 Jan 1 16(1):61-77 [abstract on PubMed] [citations onGoogle Scholar] [related articles] [full text] [order article]
Selected by | Stefano Di DonatoEvaluated 4 Jan 2007
Browse relevant SectionsView additional info
FacultyComments
Faculty Comments
Faculty Member
This timelycontribution
shows therelevance of
the proteincontext in
determining
thepathogenic
potential ofmutant
huntingtin
(mhtt) onmitochondrial
Ca++homeostasis
and
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/pubmed/17135277http://www.f1000medicine.com/pubmed/gs/17135277http://www.f1000medicine.com/pubmed/gs/17135277http://www.f1000medicine.com/related/17135277http://www.f1000medicine.com/fulltext/doi/10.1093/hmg/ddl440http://www.f1000medicine.com/fulltext/order/17135277http://www.f1000medicine.com/article/id/1058832/evaluation/sectionshttp://www.f1000medicine.com/article/id/1058832/evaluation/additionalhttp://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/pubmed/17135277http://www.f1000medicine.com/pubmed/gs/17135277http://www.f1000medicine.com/pubmed/gs/17135277http://www.f1000medicine.com/related/17135277http://www.f1000medicine.com/fulltext/doi/10.1093/hmg/ddl440http://www.f1000medicine.com/fulltext/order/17135277http://www.f1000medicine.com/article/id/1058832/evaluation/sectionshttp://www.f1000medicine.com/article/id/1058832/evaluation/additional8/8/2019 PolyQ From f1000 Medcine
10/47
respiration.
The authorselegantly
demonstratethat the first
17 aminoacids of htt
are crucial forestablishing
directinteractions
between mhttand
mitochondria,and show that
theseinteractions
drive protonleakage,
respiration
uncouplingand increasedreactive
oxygen
speciesgeneration.
This workprovides a
further
molecular linkbetween
mitochondria
andneurodegeneration in
keeping witha series of
recentcontributions
{1-3}pointing to
transcriptional repression of
thetranscriptiona
l co-activatorPGC1-alpha
as a cause ofmitochondrial
dysfunctionand disease
mechanism in
Huntingtonsdisease.
References:
8/8/2019 PolyQ From f1000 Medcine
11/47
{1} Milakovic
et al., J BiolChem 2006,
281:34785-34795
[PMID:16973623]; {2} Cui
et al., Cell2006,
127:59-69[PMID:17018
277]; {3}Weydt et al.,
Cell Metab2006, 4:349-
362[PMID:17055
784].
Competinginterests: Nopotential
interests
relevant tothis article
werereported.
Evaluated 4
Jan 2007
Stefano Di
DonatoIstituto NazionaleNeurologico
Carlo Besta-IRCCS, Italy
NEUROLOGICALDISORDERS
Confirmation
Faculty Member
This timely
contributionshows the
relevance ofthe protein
context indetermining
thepathogenic
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/17251814205216608/8/2019 PolyQ From f1000 Medcine
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potential of
mutanthuntingtin
(mhtt) onmitochondrial
Ca++homeostasis
andrespiration.
The authorselegantly
demonstratethat the first
17 aminoacids of htt
are crucial forestablishing
directinteractions
between mhtt
andmitochondria,and show that
these
interactionsdrive proton
leakage,respiration
uncoupling
and increasedreactive
oxygen
speciesgeneration.This work
provides afurther
molecular linkbetween
mitochondriaand
neurodegeneration in
keeping witha series of
recentcontributions
{1-3}pointing to
transcriptional repression of
the
transcriptional co-activator
PGC1-alpha
8/8/2019 PolyQ From f1000 Medcine
13/47
as a cause of
mitochondrialdysfunction
and diseasemechanism in
Huntingtonsdisease.
References:{1} Milakovic
et al., J BiolChem 2006,
281:34785-34795
[PMID:16973623]; {2} Cui
et al., Cell2006,
127:59-69[PMID:17018
277]; {3}
Weydt et al.,Cell Metab2006, 4:349-
362
[PMID:17055784].
Competing
interests: Nopotential
interests
relevant tothis articlewere
reported.Evaluated 4
Jan 2007
Stefano DiDonato
Istituto NazionaleNeurologico
Carlo Besta-IRCCS, Italy
NEUROLOGICALDISORDERS
Confirmation
Faculty Member
This timely
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/17251814205216608/8/2019 PolyQ From f1000 Medcine
14/47
contribution
shows therelevance of
the proteincontext in
determiningthe
pathogenicpotential of
mutanthuntingtin
(mhtt) onmitochondrial
Ca++homeostasis
andrespiration.
The authorselegantly
demonstrate
that the first17 aminoacids of htt
are crucial for
establishingdirect
interactionsbetween mhtt
and
mitochondria,and show that
these
interactionsdrive protonleakage,
respirationuncoupling
and increasedreactive
oxygenspecies
generation.This work
provides afurther
molecular linkbetween
mitochondriaand
neurodegeneration in
keeping with
a series ofrecent
contributions
8/8/2019 PolyQ From f1000 Medcine
15/47
{1-3}
pointing totranscriptiona
l repression ofthe
transcriptional co-activator
PGC1-alphaas a cause of
mitochondrialdysfunction
and diseasemechanism in
Huntingtonsdisease.
References:{1} Milakovic
et al., J BiolChem 2006,
281:34785-
34795[PMID:16973623]; {2} Cui
et al., Cell
2006,127:59-69
[PMID:17018277]; {3}
Weydt et al.,
Cell Metab2006, 4:349-
362
[PMID:17055784].
Competing
interests: Nopotential
interestsrelevant to
this articlewere
reported.Evaluated 4
Jan 2007
Stefano DiDonato
Istituto NazionaleNeurologico
Carlo Besta-
IRCCS, ItalyNEUROLOGICAL
DISORDERS
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/17251814205216608/8/2019 PolyQ From f1000 Medcine
16/47
Confirmation
Faculty MemberComments
This timely contribution shows the relevance of theprotein context in determining the pathogenic potential of
mutant huntingtin (mhtt) on mitochondrial Ca++homeostasis and respiration. The authors elegantly
demonstrate that the first 17 amino acids of htt arecrucial for establishing direct interactions between mhtt
and mitochondria, and show that these interactions drive
proton leakage, respiration uncoupling and increasedreactive oxygen species generation. This work provides a
further molecular link between mitochondria andneurodegeneration in keeping with a series of recent
contributions {1-3} pointing to transcriptional repression
of the transcriptional co-activator PGC1-alpha as a causeof mitochondrial dysfunction and disease mechanism in
Huntingtons disease. References: {1} Milakovic et al., JBiol Chem 2006, 281:34785-34795 [PMID:16973623];
{2} Cui et al., Cell 2006, 127:59-69 [PMID:17018277];{3} Weydt et al., Cell Metab 2006, 4:349-362
[PMID:17055784].
Competing interests: No potential interests relevant to
this article were reported.Evaluated 4 Jan 2007
Stefano Di DonatoIstituto Nazionale Neurologico Carlo Besta- IRCCS, ItalyNEUROLOGICAL DISORDERS
Confirmation
MicroRNA pathways modulate polyglutamine-induced neurodegeneration.Bilen J, Liu N, Burnett BG, Pittman RN, Bonini NM
Mol Cell2006 Oct 6 24(1):157-63 [abstract on PubMed] [citations on GoogleScholar] [related articles] [full text] [order article]
Selected by | Leslie ThompsonEvaluated 11 Dec 2006
Browse relevant SectionsView additional info
Faculty
Comments
Faculty Comments
Faculty Member
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/pubmed/17018300http://www.f1000medicine.com/pubmed/gs/17018300http://www.f1000medicine.com/pubmed/gs/17018300http://www.f1000medicine.com/related/17018300http://www.f1000medicine.com/fulltext/doi/10.1016/j.molcel.2006.07.030http://www.f1000medicine.com/fulltext/order/17018300http://www.f1000medicine.com/article/id/1050457/evaluation/sectionshttp://www.f1000medicine.com/article/id/1050457/evaluation/additionalhttp://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/pubmed/17018300http://www.f1000medicine.com/pubmed/gs/17018300http://www.f1000medicine.com/pubmed/gs/17018300http://www.f1000medicine.com/related/17018300http://www.f1000medicine.com/fulltext/doi/10.1016/j.molcel.2006.07.030http://www.f1000medicine.com/fulltext/order/17018300http://www.f1000medicine.com/article/id/1050457/evaluation/sectionshttp://www.f1000medicine.com/article/id/1050457/evaluation/additional8/8/2019 PolyQ From f1000 Medcine
17/47
This is thefirst study to
show a rolefor MicroRNAs
(miRNAs) inpolyglutamine
repeatneurodegener
ative diseasein vivo. It
alsohighlights a
potential rolein tau
toxicity.MicroRNAs
are a recently
discoveredand importantmechanism of
regulation of
cellularprocesses,
however, littleis known
about their
possible rolein
neurodegener
ation. Theauthors foundthat when
genes thatare critical for
miRNAprocessing
are reducedin activity in
Drosophila,an
enhancementof
polyglutaminerepeat
toxicity isobserved in
bothDrosophila
and human
cells. Thesepathways
have been
8/8/2019 PolyQ From f1000 Medcine
18/47
implicated in
developmental processes
and cancerand here the
authors testtheir role in
neuronalmaintenance.
Of greatinterest, the
miRNAbantam, ban,
is amodulator of
bothpolyglutamine
and tautoxicity in
flies. These
studies haveimplicationsfor
neurodegener
ation forseveral
reasons.Firstly, of the
genes tested,
only reductionof those
involved in
miRNAprocessing,but not siRNA
processingmodulated
polyQdegeneration.
Secondly, themiRNA, ban,
modulatesdegeneration
of polyQ andtau,
apparentlydownstream
of inherentprotein
toxicity.Thirdly, these
findings now
expand therole of miRNA
function to
8/8/2019 PolyQ From f1000 Medcine
19/47
include
neurodegeneration and
provide anovel
therapeutictarget.
Competinginterests: No
potentialinterests
relevant tothis article
werereported.
Evaluated 11Dec 2006
LeslieThompsonUniversity of
California Irvine,
United States ofAmerica
NEUROLOGICALDISORDERS
New Finding
Faculty Member
This is thefirst study to
show a rolefor MicroRNAs
(miRNAs) inpolyglutamine
repeat
neurodegenerative disease
in vivo. It
alsohighlights a
potential rolein tau
toxicity.MicroRNAs
are a recentlydiscovered
and importantmechanism of
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/14508239563611368/8/2019 PolyQ From f1000 Medcine
20/47
regulation of
cellularprocesses,
however, littleis known
about theirpossible role
inneurodegener
ation. Theauthors found
that whengenes that
are critical formiRNA
processingare reduced
in activity inDrosophila,
an
enhancementofpolyglutamine
repeat
toxicity isobserved in
bothDrosophila
and human
cells. Thesepathways
have been
implicated indevelopmental processes
and cancerand here the
authors testtheir role in
neuronalmaintenance.
Of greatinterest, the
miRNAbantam, ban,
is amodulator of
bothpolyglutamine
and tautoxicity in
flies. These
studies haveimplications
for
8/8/2019 PolyQ From f1000 Medcine
21/47
neurodegener
ation forseveral
reasons.Firstly, of the
genes tested,only reduction
of thoseinvolved in
miRNAprocessing,
but not siRNAprocessing
modulatedpolyQ
degeneration.Secondly, the
miRNA, ban,modulates
degeneration
of polyQ andtau,apparently
downstream
of inherentprotein
toxicity.Thirdly, these
findings now
expand therole of miRNA
function to
includeneurodegeneration and
provide anovel
therapeutictarget.
Competinginterests: No
potentialinterests
relevant tothis article
werereported.
Evaluated 11Dec 2006
LeslieThompson
University of
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/14508239563611368/8/2019 PolyQ From f1000 Medcine
22/47
California Irvine,
United States ofAmerica
NEUROLOGICALDISORDERS
New Finding
Faculty Member
This is the
first study to
show a rolefor MicroRNAs
(miRNAs) inpolyglutamine
repeat
neurodegenerative disease
in vivo. Italso
highlights apotential role
in tautoxicity.
MicroRNAsare a recently
discoveredand important
mechanism of
regulation ofcellularprocesses,
however, littleis known
about theirpossible role
inneurodegener
ation. The
authors foundthat when
genes that
are critical formiRNA
processingare reduced
in activity inDrosophila,
anenhancement
ofpolyglutamine
8/8/2019 PolyQ From f1000 Medcine
23/47
repeat
toxicity isobserved in
bothDrosophila
and humancells. These
pathwayshave been
implicated indevelopmenta
l processesand cancer
and here theauthors test
their role inneuronal
maintenance.Of great
interest, the
miRNAbantam, ban,is a
modulator of
bothpolyglutamine
and tautoxicity in
flies. These
studies haveimplications
for
neurodegeneration forseveral
reasons.Firstly, of the
genes tested,only reduction
of thoseinvolved in
miRNAprocessing,
but not siRNAprocessing
modulatedpolyQ
degeneration.Secondly, the
miRNA, ban,modulates
degeneration
of polyQ andtau,
apparently
8/8/2019 PolyQ From f1000 Medcine
24/47
downstream
of inherentprotein
toxicity.Thirdly, these
findings nowexpand the
role of miRNAfunction to
includeneurodegener
ation andprovide a
noveltherapeutic
target.
Competing
interests: No
potentialinterestsrelevant to
this article
werereported.
Evaluated 11Dec 2006
LeslieThompson
University of
California Irvine,United States ofAmerica
NEUROLOGICALDISORDERS
New Finding
Faculty MemberComments
This is the first study
to show a role forMicroRNAs (miRNAs)
in polyglutaminerepeat
neurodegenerativedisease in vivo. It
also highlights apotential role in tau
toxicity. MicroRNAsare a recently
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/about/biography/14508239563611368/8/2019 PolyQ From f1000 Medcine
25/47
discovered and
importantmechanism of
regulation of cellularprocesses, however,
little is known abouttheir possible role in
neurodegeneration.The authors found
that when genes thatare critical for miRNA
processing arereduced in activity in
Drosophila, anenhancement of
polyglutamine repeattoxicity is observed
in both Drosophilaand human cells.
These pathways have
been implicated indevelopmentalprocesses and cancer
and here the authors
test their role inneuronal
maintenance. Ofgreat interest, the
miRNA bantam, ban,
is a modulator ofboth polyglutamine
and tau toxicity in
flies. These studieshave implications forneurodegeneration
for several reasons.Firstly, of the genes
tested, onlyreduction of those
involved in miRNAprocessing, but not
siRNA processingmodulated polyQ
degeneration.Secondly, the
miRNA, ban,modulates
degeneration ofpolyQ and tau,
apparentlydownstream of
inherent protein
toxicity. Thirdly,these findings now
expand the role of
8/8/2019 PolyQ From f1000 Medcine
26/47
miRNA function to
includeneurodegeneration
and provide a noveltherapeutic target.
Competing interests:No potential interests
relevant to thisarticle were reported.
Evaluated 11 Dec2006
Leslie Thompson
University of California Irvine, United Statesof America
NEUROLOGICAL DISORDERS
New Finding
JNK mediates pathogenic effects of polyglutamine-expanded androgen
receptor on fast axonal transport.Morfini G, Pigino G, Szebenyi G, You Y, Pollema S, Brady ST
Nat Neurosci2006 Jul 9(7):907-16 [abstract on PubMed] [citations on GoogleScholar] [related articles] [full text] [order article]
Selected by | Albert La SpadaEvaluated 21 Aug 2006
Browse relevant SectionsView additional info
Faculty
Comments
Faculty Comments
Faculty Member
The findingsof this paper
are important
as they addto a growing
body ofliterature
implicating
altered axonaltransport in
motor neurondisease and
spastic
http://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/pubmed/16751763http://www.f1000medicine.com/pubmed/gs/16751763http://www.f1000medicine.com/pubmed/gs/16751763http://www.f1000medicine.com/related/16751763http://www.f1000medicine.com/fulltext/doi/10.1038/nn1717http://www.f1000medicine.com/fulltext/order/16751763http://www.f1000medicine.com/article/id/14581/evaluation/sectionshttp://www.f1000medicine.com/article/id/14581/evaluation/additionalhttp://www.f1000medicine.com/about/biography/1450823956361136http://www.f1000medicine.com/pubmed/16751763http://www.f1000medicine.com/pubmed/gs/16751763http://www.f1000medicine.com/pubmed/gs/16751763http://www.f1000medicine.com/related/16751763http://www.f1000medicine.com/fulltext/doi/10.1038/nn1717http://www.f1000medicine.com/fulltext/order/16751763http://www.f1000medicine.com/article/id/14581/evaluation/sectionshttp://www.f1000medicine.com/article/id/14581/evaluation/additional8/8/2019 PolyQ From f1000 Medcine
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paraplegias,
and highlightJun-N-
terminalkinase (JNK)
as a potentialtherapeutic
target in suchdisorders. The
studypresents data
that supportsa role for
altered axonaltransport in
thepathogenesis
of X-linkedspinal and
bulbar
muscularatrophy, aninherited
polyglutamine
repeatdisease
characterizedby lower
motor neuron
degeneration.The authors
demonstrate
thatactivation ofJNK by
mutantandrogen
receptorprotein may
contribute tothe motor
neurondegeneration.
Competing
interests: Nopotential
interests
relevant tothis article
were
reported.Evaluated 21
Aug 2006
8/8/2019 PolyQ From f1000 Medcine
28/47
Albert LaSpada
University ofWashington,
United States ofAmerica
NEUROLOGICALDISORDERS
Hypothesis
New Finding
Faculty Member
The findings
of this paper
are importantas they add
to a growingbody of
literatureimplicating
altered axonaltransport in
motor neurondisease and
spasticparaplegias,
and highlight
Jun-N-terminalkinase (JNK)
as a potentialtherapeutic
target in suchdisorders. The
studypresents data
that supports
a role foraltered axonal
transport in
thepathogenesis
of X-linkedspinal and
bulbarmuscular
atrophy, aninherited
polyglutaminerepeat
http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/14944044441279028/8/2019 PolyQ From f1000 Medcine
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disease
characterizedby lower
motor neurondegeneration.
The authorsdemonstrate
thatactivation of
JNK bymutant
androgenreceptor
protein maycontribute to
the motorneuron
degeneration.
Competing
interests: Nopotential
interests
relevant tothis article
werereported.
Evaluated 21Aug 2006
Albert La
SpadaUniversity of
Washington,United States of
AmericaNEUROLOGICAL
DISORDERS
HypothesisNew Finding
Faculty Member
The findings
of this paperare important
as they addto a growing
body ofliterature
http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/14944044441279028/8/2019 PolyQ From f1000 Medcine
30/47
implicating
altered axonaltransport in
motor neurondisease and
spasticparaplegias,
and highlightJun-N-
terminalkinase (JNK)
as a potentialtherapeutic
target in suchdisorders. The
studypresents data
that supportsa role for
altered axonal
transport inthepathogenesis
of X-linked
spinal andbulbar
muscularatrophy, an
inherited
polyglutaminerepeat
disease
characterizedby lowermotor neuron
degeneration.The authors
demonstratethat
activation ofJNK by
mutantandrogen
receptorprotein may
contribute tothe motor
neurondegeneration.
Competing
interests: Nopotential
interests
8/8/2019 PolyQ From f1000 Medcine
31/47
relevant to
this articlewere
reported.Evaluated 21
Aug 2006
Albert LaSpada
University ofWashington,
United States ofAmerica
NEUROLOGICALDISORDERS
Hypothesis
New Finding
Faculty MemberComments
The findingsof this paper
are importantas they add
to a growingbody of
literatureimplicating
altered
axonaltransport inmotor neuron
disease andspastic
paraplegias,and highlight
Jun-N-terminal
kinase (JNK)
as a potentialtherapeutic
target in such
disorders.The study
presents datathat supports
a role foraltered
axonaltransport in
thepathogenesis
http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/about/biography/14944044441279028/8/2019 PolyQ From f1000 Medcine
32/47
of X-linked
spinal andbulbar
muscularatrophy, an
inheritedpolyglutamin
e repeatdisease
characterizedby lower
motor neurondegeneration.
The authorsdemonstrate
thatactivation of
JNK bymutant
androgen
receptorprotein maycontribute to
the motor
neurondegeneration.
Competinginterests: No
potentialinterests
relevant tothis article
werereported.
Evaluated 21Aug 2006
Albert La Spada
University of Washington, United Statesof America
NEUROLOGICAL DISORDERS
Hypothesis New Finding
Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to
huntingtin.Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z,
Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MRCell2006 Jun 16 125(6):1179-91 [abstract on PubMed] [citations on Google Scholar] [related a
text] [order article]
Selected by | Stefano Di Donato
Evaluated 13 Jul 2006
http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/pubmed/16777606http://www.f1000medicine.com/pubmed/gs/16777606http://www.f1000medicine.com/related/16777606http://www.f1000medicine.com/fulltext/doi/10.1016/j.cell.2006.04.026http://www.f1000medicine.com/fulltext/order/16777606http://www.f1000biology.com/article/id/1032808http://www.f1000medicine.com/about/biography/1494404444127902http://www.f1000medicine.com/pubmed/16777606http://www.f1000medicine.com/pubmed/gs/16777606http://www.f1000medicine.com/related/16777606http://www.f1000medicine.com/fulltext/doi/10.1016/j.cell.2006.04.026http://www.f1000medicine.com/fulltext/order/16777606http://www.f1000medicine.com/article/id/14544/evaluation/sectionshttp://www.f1000medicine.com/article/id/14544/evaluation/additional8/8/2019 PolyQ From f1000 Medcine
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FacultyComments
Faculty Comments
Faculty Member
This is the
firstdemonstratio
n that aspecific
huntingtin(htt)
fragmentgenerated by
the protease
caspase-6 istheneurotoxic
polyglutamine(polyQ)-
containingpeptide
causingneural
dysfunction,neurodegener
ation andexcitotoxicity
in a mousemodel forHuntingdon's
disease (HD),thus arguing
for caspase-6
specificinhibitors to
be used asputative
therapeuticagents. The
authors haveused a
creative andbrave
strategy bygenerating
YAC128-HDmice carrying
mutations atthe different
8/8/2019 PolyQ From f1000 Medcine
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caspase sites
in a modelwhich is
known to bestreproduce the
human clinicaland
neuropathological findings.
The authorsdemonstrate
that thecaspase-6-
resistantmice, but not
the caspase-3-resistant
mice,generated by
mutation of
the caspase-6site atposition 586,
are protected
fromneurodegener
ation andmotor
dysfunction,
also escapingglutamate
and NMDAR-
mediatedexcitotoxicity.
Competinginterests: No
potentialinterests
relevant tothis article
werereported.
Evaluated 13Jul 2006
Stefano Di
Donato
Istituto NazionaleNeurologico
Carlo Besta-
IRCCS, ItalyNEUROLOGICAL
DISORDERS
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/17251814205216608/8/2019 PolyQ From f1000 Medcine
35/47
New Finding
Faculty Member
This is thefirst
demonstration that a
specifichuntingtin
(htt)
fragmentgenerated by
the proteasecaspase-6 is
the
neurotoxicpolyglutamine
(polyQ)-containing
peptidecausing
neuraldysfunction,
neurodegeneration and
excitotoxicityin a mouse
model for
Huntingdon'sdisease (HD),thus arguing
for caspase-6specific
inhibitors tobe used as
putativetherapeutic
agents. The
authors haveused a
creative and
bravestrategy by
generatingYAC128-HD
mice carryingmutations at
the differentcaspase sites
in a modelwhich is
8/8/2019 PolyQ From f1000 Medcine
36/47
known to best
reproduce thehuman clinical
andneuropatholo
gical findings.The authors
demonstratethat the
caspase-6-resistant
mice, but notthe caspase-
3-resistantmice,
generated bymutation of
the caspase-6site at
position 586,
are protectedfromneurodegener
ation and
motordysfunction,
also escapingglutamate
and NMDAR-
mediatedexcitotoxicity.
Competing
interests: Nopotential
interestsrelevant to
this articlewere
reported.Evaluated 13
Jul 2006
Stefano DiDonato
Istituto NazionaleNeurologico
Carlo Besta-
IRCCS, ItalyNEUROLOGICAL
DISORDERS
New Finding
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/17251814205216608/8/2019 PolyQ From f1000 Medcine
37/47
Faculty Member
This is thefirst
demonstration that a
specifichuntingtin
(htt)fragment
generated bythe protease
caspase-6 isthe
neurotoxic
polyglutamine
(polyQ)-containing
peptidecausing
neuraldysfunction,
neurodegeneration and
excitotoxicityin a mouse
model forHuntingdon's
disease (HD),
thus arguingfor caspase-6specific
inhibitors tobe used as
putativetherapeutic
agents. Theauthors have
used acreative and
brave
strategy bygenerating
YAC128-HDmice carrying
mutations at
the differentcaspase sites
in a modelwhich is
known to best
8/8/2019 PolyQ From f1000 Medcine
38/47
reproduce the
human clinicaland
neuropathological findings.
The authorsdemonstrate
that thecaspase-6-
resistantmice, but not
the caspase-3-resistant
mice,generated by
mutation ofthe caspase-6
site atposition 586,
are protected
fromneurodegeneration and
motor
dysfunction,also escaping
glutamateand NMDAR-
mediated
excitotoxicity.
Competinginterests: No
potentialinterests
relevant tothis article
werereported.
Evaluated 13Jul 2006
Stefano Di
DonatoIstituto Nazionale
NeurologicoCarlo Besta-
IRCCS, Italy
NEUROLOGICALDISORDERS
New Finding
Faculty Member Comments
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000medicine.com/about/biography/17251814205216608/8/2019 PolyQ From f1000 Medcine
39/47
This is the first
demonstration that aspecific huntingtin
(htt) fragmentgenerated by the
protease caspase-6is the neurotoxic
polyglutamine(polyQ)-containing
peptide causingneural dysfunction,
neurodegenerationand excitotoxicity in
a mouse model for
Huntingdon's disease
(HD), thus arguingfor caspase-6 specific
inhibitors to be usedas putative
therapeutic agents.The authors have
used a creative andbrave strategy by
generating YAC128-HD mice carrying
mutations at thedifferent caspase
sites in a model
which is known tobest reproduce thehuman clinical and
neuropathologicalfindings. The authors
demonstrate that thecaspase-6-resistant
mice, but not thecaspase-3-resistant
mice, generated bymutation of the
caspase-6 site at
position 586, areprotected from
neurodegenerationand motor
dysfunction, also
escaping glutamateand NMDAR-
mediatedexcitotoxicity.
8/8/2019 PolyQ From f1000 Medcine
40/47
Competing interests:No potential interests
relevant to thisarticle were reported.
Evaluated 13 Jul2006
Stefano Di Donato
Istituto Nazionale Neurologico Carlo Besta-IRCCS, Italy
NEUROLOGICAL DISORDERS
New Finding
Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due tohuntingtin.
Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z,
Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MRCell2006 Jun 16 125(6):1179-91 [abstract on PubMed] [citations on Google Scholar] [related a
[full text] [order article]
Selected by | M. Flint Beal
Evaluated 21 Jun 2006Relevant Sections
FacultyComments
Faculty Comments
Faculty Member
This is an
importantpaper that
demonstratesthat a
caspase-6site is critical
for
Huntington'sDiseasepathogenesis.
It has beenknown for
sometime
that cleavageof huntingtin
to produce N-
terminal
http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000biology.com/pubmed/16777606http://www.f1000biology.com/pubmed/gs/16777606http://www.f1000biology.com/related/16777606http://www.f1000biology.com/fulltext/doi/10.1016/j.cell.2006.04.026http://www.f1000biology.com/fulltext/order/16777606http://www.f1000biology.com/article/id/1032808/evaluation/sectionshttp://www.f1000medicine.com/article/id/14544http://www.f1000medicine.com/about/biography/1725181420521660http://www.f1000biology.com/pubmed/16777606http://www.f1000biology.com/pubmed/gs/16777606http://www.f1000biology.com/related/16777606http://www.f1000biology.com/fulltext/doi/10.1016/j.cell.2006.04.026http://www.f1000biology.com/fulltext/order/16777606http://www.f1000biology.com/article/id/1032808/evaluation/sections8/8/2019 PolyQ From f1000 Medcine
41/47
fragments
markedlyaffects its
toxicity. Thesmaller N-
terminalfragments
thenaccumulate in
the nucleus.In the present
paper, it wasdemonstrated
that caspase-6 resistant
proteinbecomes
neuroprotective against
cytotoxic
insults similarto wildtypehuntingtin
protein. The
paperdemonstrates
that theprotection
from toxicity
is criticallydependent on
mutating the
caspase-6site in thehuntingtin
protein, asopposed to a
number ofother caspase
sites. Thecaspase-6
resistant formhelps protect
culturedneurons from
NMDAexcitotoxicity.
Thesefindings are
important inthat they
identify
caspase-6 asa potential
therapeutic
8/8/2019 PolyQ From f1000 Medcine
42/47
site for the
developmentof
therapeuticsfor
Huntington'sDisease.
Competinginterests:
None declaredEvaluated 21
Jun 2006
M. Flint BealWeill Medical
College of CornellUniversity ,
United States of
AmericaNEUROSCIENCE
New Finding
Faculty Member
This is animportant
paper that
demonstratesthat acaspase-6
site is criticalfor
Huntington'sDisease
pathogenesis.It has been
known for
sometimethat cleavage
of huntingtin
to produce N-terminal
fragmentsmarkedly
affects itstoxicity. The
smaller N-terminal
fragmentsthen
http://www.f1000biology.com/about/biography/2098691424870705http://www.f1000biology.com/about/biography/20986914248707058/8/2019 PolyQ From f1000 Medcine
43/47
accumulate in
the nucleus.In the present
paper, it wasdemonstrated
that caspase-6 resistant
proteinbecomes
neuroprotective against
cytotoxicinsults similar
to wildtypehuntingtin
protein. Thepaper
demonstratesthat the
protection
from toxicityis criticallydependent on
mutating the
caspase-6site in the
huntingtinprotein, as
opposed to a
number ofother caspase
sites. The
caspase-6resistant formhelps protect
culturedneurons from
NMDAexcitotoxicity.
Thesefindings are
important inthat they
identifycaspase-6 as
a potentialtherapeutic
site for thedevelopment
oftherapeutics
for
Huntington'sDisease.
8/8/2019 PolyQ From f1000 Medcine
44/47
Competinginterests:
None declaredEvaluated 21
Jun 2006
M. Flint BealWeill Medical
College of CornellUniversity ,
United States ofAmerica
NEUROSCIENCE
New Finding
Faculty Member
This is animportant
paper thatdemonstrates
that acaspase-6
site is criticalfor
Huntington'sDisease
pathogenesis.
It has beenknown forsometime
that cleavageof huntingtin
to produce N-terminal
fragmentsmarkedly
affects its
toxicity. Thesmaller N-
terminal
fragmentsthen
accumulate inthe nucleus.
In the presentpaper, it was
demonstratedthat caspase-
6 resistantprotein
http://www.f1000biology.com/about/biography/2098691424870705http://www.f1000biology.com/about/biography/20986914248707058/8/2019 PolyQ From f1000 Medcine
45/47
becomes
neuroprotective against
cytotoxicinsults similar
to wildtypehuntingtin
protein. Thepaper
demonstratesthat the
protectionfrom toxicity
is criticallydependent on
mutating thecaspase-6
site in thehuntingtin
protein, as
opposed to anumber ofother caspase
sites. The
caspase-6resistant form
helps protectcultured
neurons from
NMDAexcitotoxicity.
These
findings areimportant inthat they
identifycaspase-6 as
a potentialtherapeutic
site for thedevelopment
oftherapeutics
forHuntington's
Disease.
Competing
interests:None declared
Evaluated 21
Jun 2006
M. Flint Beal
http://www.f1000biology.com/about/biography/2098691424870705http://www.f1000biology.com/about/biography/20986914248707058/8/2019 PolyQ From f1000 Medcine
46/47
Weill Medical
College of CornellUniversity ,
United States ofAmerica
NEUROSCIENCE
New FindingFaculty Member
Comments
This is an
importantpaper that
demonstratesthat a caspase-
6 site is critical
forHuntington's
Diseasepathogenesis.
It has beenknown for
sometime thatcleavage of
huntingtin toproduce N-
terminalfragments
markedly
affects itstoxicity. Thesmaller N-
terminalfragments then
accumulate inthe nucleus. In
the presentpaper, it was
demonstrated
that caspase-6resistant
protein
becomesneuroprotective
againstcytotoxic
insults similarto wildtype
huntingtinprotein. The
paperdemonstrates
8/8/2019 PolyQ From f1000 Medcine
47/47
that the
protection fromtoxicity is
criticallydependent on
mutating thecaspase-6 site
in thehuntingtin
protein, asopposed to a
number ofother caspase
sites. Thecaspase-6
resistant formhelps protect
culturedneurons from
NMDA
excitotoxicity.These findingsare important
in that they
identifycaspase-6 as a
potentialtherapeutic site
for the
development oftherapeutics for
Huntington's
Disease.
Competinginterests: None
declaredEvaluated 21
Jun 2006
M. Flint BealWeill Medical College of Cornell University
, United States of AmericaNEUROSCIENCE
New Finding
http://www.f1000biology.com/about/biography/2098691424870705http://www.f1000biology.com/about/biography/2098691424870705Top Related