polyq from f1000 medcine

8/8/2019 PolyQ From f1000 Medcine

1/47

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/17384639


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


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/1450823956361136


4/47

chromosomal

proteins(HMGB1/2),

which are keyregulators of

geneexpression

and DNAintegrity,


in models ofboth


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


in HD andSCA1 and

suggests anew function

for HMGB1/2

inpolyglutamine

pathology.


5/47

Competing

interests: Nopotential


this articlewere


Apr 2007

LeslieThompson

University ofCalifornia Irvine,


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


6/47

that the

ubiquitousand abundant

non-histonechromosomal

proteins(HMGB1/2),


geneexpression

and DNAintegrity,


in models ofboth


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


in HD and

SCA1 andsuggests a

new function


7/47

for HMGB1/2

inpolyglutamine

pathology.

Competing



this articlewere


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


8/47

reports the

novel findingthat the

ubiquitous andabundant non-

histonechromosomal

proteins(HMGB1/2),


gene expressionand DNA

integrity, showreduced soluble

levels in modelsof both


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


9/47

interests: No

potentialinterests

relevant to thisarticle were


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/additional


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:


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


Confirmation

Faculty Member

This timely

contributionshows the

relevance ofthe protein

context indetermining

thepathogenic


12/47

potential of

mutanthuntingtin


Ca++homeostasis

andrespiration.


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


mitochondriaand

neurodegeneration in

keeping witha series of

recentcontributions

{1-3}pointing to

transcriptional repression of

the

transcriptional co-activator

PGC1-alpha


13/47

as a cause of

mitochondrialdysfunction

and diseasemechanism in

Huntingtonsdisease.

References:{1} Milakovic


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

relevant tothis articlewere


Jan 2007

Stefano DiDonato

Istituto NazionaleNeurologico

Carlo Besta-IRCCS, Italy


Confirmation

Faculty Member

This timely


14/47

contribution

shows therelevance of

the proteincontext in

determiningthe

pathogenicpotential of

mutanthuntingtin


Ca++homeostasis

andrespiration.


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


mitochondriaand

neurodegeneration in

keeping with

a series ofrecent

contributions


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


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



this articlewere


Jan 2007

Stefano DiDonato


Carlo Besta-

IRCCS, ItalyNEUROLOGICAL

DISORDERS


16/47

Confirmation


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


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/additional


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


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


19/47

include

neurodegeneration and

provide anovel

therapeutictarget.

Competinginterests: No

potentialinterests


werereported.

Evaluated 11Dec 2006

LeslieThompsonUniversity of

California Irvine,



New Finding

Faculty Member

This is thefirst study to



repeat

neurodegenerative disease

in vivo. It

alsohighlights a

potential rolein tau

toxicity.MicroRNAs

are a recentlydiscovered

and importantmechanism of


20/47

regulation of

cellularprocesses,


about theirpossible role

inneurodegener

ation. Theauthors found

that whengenes that

are critical formiRNA

processingare reduced

in activity inDrosophila,

an

enhancementofpolyglutamine

repeat


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


21/47

neurodegener

ation forseveral


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


findings now

expand therole of miRNA

function to

includeneurodegeneration and

provide anovel

therapeutictarget.


potentialinterests


werereported.


LeslieThompson

University of


22/47

California Irvine,



New Finding

Faculty Member

This is the

first study to



repeat

neurodegenerative disease

in vivo. Italso

highlights apotential role

in tautoxicity.

MicroRNAsare a recently

discoveredand important

mechanism of

regulation ofcellularprocesses,


about theirpossible role

inneurodegener

ation. The

authors foundthat when

genes that

are critical formiRNA

processingare reduced

in activity inDrosophila,

anenhancement

ofpolyglutamine


23/47

repeat


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


genes tested,only reduction

of thoseinvolved in

miRNAprocessing,

but not siRNAprocessing

modulatedpolyQ



degeneration

of polyQ andtau,

apparently


24/47

downstream

of inherentprotein


findings nowexpand the

role of miRNAfunction to

includeneurodegener

ation andprovide a

noveltherapeutic

target.

Competing

interests: No

potentialinterestsrelevant to

this article

werereported.


LeslieThompson

University of

California Irvine,United States ofAmerica


New Finding


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


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 ofpolyQ and tau,

apparentlydownstream of

inherent protein

toxicity. Thirdly,these findings now

expand the role of


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


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/additional


27/47

paraplegias,

and highlightJun-N-

terminalkinase (JNK)

as a potentialtherapeutic

target in suchdisorders. The

studypresents data

that supportsa role for


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


were


Aug 2006


28/47

Albert LaSpada

University ofWashington,



Hypothesis

New Finding

Faculty Member

The findings

of this paper

are importantas they add

to a growingbody of

literatureimplicating



spasticparaplegias,

and highlight

Jun-N-terminalkinase (JNK)



studypresents data

that supports

a role foraltered axonal

transport in

thepathogenesis

of X-linkedspinal and

bulbarmuscular

atrophy, aninherited

polyglutaminerepeat


29/47

disease


motor neurondegeneration.

The authorsdemonstrate

thatactivation of

JNK bymutant

androgenreceptor

protein maycontribute to

the motorneuron

degeneration.

Competing


interests


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


30/47

implicating



spasticparaplegias,

and highlightJun-N-

terminalkinase (JNK)



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


31/47

relevant to

this articlewere


Aug 2006

Albert LaSpada

University ofWashington,



Hypothesis

New Finding


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)


target in such

disorders.The study

presents datathat supports

a role foraltered

axonaltransport in

thepathogenesis


32/47

of X-linked

spinal andbulbar

muscularatrophy, an

inheritedpolyglutamin

e repeatdisease


motor neurondegeneration.


thatactivation of

JNK bymutant

androgen

receptorprotein maycontribute to

the motor

neurondegeneration.


potentialinterests


werereported.

Evaluated 21Aug 2006

Albert La Spada

University of Washington, United Statesof America


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/additional


33/47

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


34/47

caspase sites

in a modelwhich is

known to bestreproduce the

human clinicaland

neuropathological findings.


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.


potentialinterests


werereported.

Evaluated 13Jul 2006

Stefano Di

Donato


Carlo Besta-


DISORDERS


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,


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


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-


Competing



this articlewere


Jul 2006

Stefano DiDonato


Carlo Besta-


DISORDERS

New Finding


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,


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


38/47

reproduce the

human clinicaland

neuropathological findings.


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.


potentialinterests


werereported.

Evaluated 13Jul 2006

Stefano Di

DonatoIstituto Nazionale

NeurologicoCarlo Besta-

IRCCS, Italy


New Finding

Faculty Member Comments


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-



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


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/sections


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


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/2098691424870705


43/47

accumulate in

the nucleus.In the present

paper, it wasdemonstrated

that caspase-6 resistant

proteinbecomes


cytotoxicinsults similar

to wildtypehuntingtin

protein. Thepaper

demonstratesthat the

protection

from toxicityis criticallydependent on

mutating the

caspase-6site in the

huntingtinprotein, as

opposed to a


sites. The

caspase-6resistant formhelps protect


NMDAexcitotoxicity.

Thesefindings are

important inthat they

identifycaspase-6 as

a potentialtherapeutic

site for thedevelopment

oftherapeutics

for

Huntington'sDisease.


44/47

Competinginterests:

None declaredEvaluated 21

Jun 2006

M. Flint BealWeill Medical



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


45/47

becomes


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


46/47

Weill Medical



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


47/47

that the

protection fromtoxicity is

criticallydependent on

mutating thecaspase-6 site

in thehuntingtin

protein, asopposed to a


sites. Thecaspase-6

resistant formhelps protect


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

polyq from f1000 medcine

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