Heat Shock Response

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Heat shock response andinsulin-associated neurodegeneration

Michael J. Urban1

, Rick T. Dobrowsky2

and Brian S.J. Blagg3

1Neuroscience

Graduate

Program,

The

University

of

Kansas,

Lawrence,

KS

66045,

USA2Department

of

Pharmacology

and

Toxicology,

The

University

of

Kansas,

Lawrence,

KS

66045,

USA3Department

of

Medicinal

Chemistry,

The

University

of

Kansas,

Lawrence,

KS

66045,

USA

Dysfunctional insulin and insulin-like growth factor-I

(IGF-I) signaling contributes to the pathological progres-

sion of diabetes, diabetic peripheral neuropathy (DPN),

Alzheimers (AD), Parkinsons (PD) and Huntingtons

diseases (HD). Despite their prevalence, there are limited

therapeutic options available for the treatment of these

neurodegenerative disorders. Therefore, establishing a

link between insulin/IGF-I and the pathoetiology of

these diseases may provide alternative approaches to-

ward their management. Many of the heat shock pro-

teins (Hsps) are well-known molecular chaperones that

solubilize and clear damagedproteinsand protein aggre-

gates.

Recent

studies

suggest

that

modulating

Hsps

may

represent a promising therapeutic avenue for improving

insulin

and

IGF-I

signaling.

Pharmacological

induction

of

the heat shock response (HSR) may intersect with insu-

lin/IGF-I signaling to improve aspects of neurodegener-

ative phenotypes. Herein, we review the intersection

between Hsps and the insulin/IGF systems under normal

and pathological conditions. The discussion will empha-

size the potential of non-toxic HSR inducers as viabletherapeutic agents.

Diabetic neuropathy and heat shock proteins

The administration of extracted pancreatic insulin in 1922

marked

the

first

effective

therapeutic

option

to

combat

diabetes

and

associated

peripheral

neuropathy.

Although

controlled insulin therapy significantly decelerates the

rate of progression of acute and chronic diabetic complica-

tions,

they

still

develop

and

represent

a

significant

risk

to

the

overall

deterioration

of

the

health

of

the

individual.

DPN is the overall attrition of sensory nerve fibers that

results

from

diabetes.

Treatments

for

DPN

generally

offer

monosymptomatic

relief

(e.g.

analgesics

to

mitigate

painfulneuropathy) or specifically inhibit single, putative patho-

genic

mechanisms

associated

with

diabetes-induced

hyper-

glycemia

[e.g.

antioxidants,

aldose

reductase

inhibitors,

and poly(ADP-ribose) polymerase (PARP) inhibitors]

[1,2].

Mismanaged

insulin

therapy

can

also

generate

symp-

toms

of

insulin

shock

(acute

hyperinsulinism),

depriving

the

brain

of

essential

glucose,

or

diabetic

encephalopathy

(hypoinsulinism) [3]. For this reason, treatment of DPN

can

benefit

from

a

more

multifaceted

therapeutic

ap-

proach.

In

addition

to

managing

non-neuronal

postprandi-

al glucose uptake, insulin and IGF signaling are required

during

early

neurological

development

and

to

maintain

neuronal viability and function throughout the nervous

system

[47].

Several

components

of

insulin

and

insulin-

like growth factor-I (IGF-I) signaling, including insulin

receptors

(commonly

mutated

in

insulin-resistant

patients)

and

IGF-I

receptors,

rely

upon

heat

shock

pro-

teins (Hsps) for post-translational modifications and integ-

rity [811]. Here we review Hsps and their role within

normal and pathological insulin/IGF systems with an em-

phasis upon their potential as therapeutic targets.

The heat shock response

Several

Hsps

serve

as

molecular

chaperones

that

assist

in

the folding of nascent polypeptides, or client proteins, into

their

mature

conformations

[1215]. These

chaperones

also

assist

in

the

refolding

of

damaged

proteins

that

arise

under stressed conditions, such as nutrient deprivation,

oxidative

and

nitrosative

stress,

and

assorted

insults

to

the

cell

[1215]. Additionally, Hsps serve as intracellular tri-

age units that refold damaged proteins, tag irreparable

proteins for proteolytic degradation, stabilize protein com-plexes, solubilize protein aggregates and facilitate intra-

cellular

trafficking

[1216].

Heat

shock

protein

90

(Hsp90)

and

heat

shock

factor

1

(HSF1)

Hsp90 is a 90 kDa homodimeric cytosolic protein that

interacts

with

more

than

200

client

proteins

and 50 co-

chaperones

[1215,17]. Although all the molecular details

by which Hsp90 folds client proteins remain unresolved,

the molecular

components

of

the

folding

machinery

have

been

well-studied.

The

co-chaperones

Hsp70

and

Hsp40

bind polypeptide substrates and are recruited into a het-

eroprotein

complex

with

Hsp90

and

Hsp70/Hsp90-organiz-ing protein (HOP) [17]. This stabilized complex enables

client

protein

transfer

to

the

Hsp90

homodimer,

thereby

permitting Hsp70, Hsp40 and HOP dissociation in some

cases

[17]. Additional

co-chaperones

and

immunophilins

aid ATP

binding

within

the

Hsp90

N-terminal

nucleotide-

binding domain, promoting N-termini dimerization and

clamping

of

the

client

protein

[17]. Co-chaperone

p23

further

stabilizes

the

clamped

protein

complex

and

mod-

ulates nucleotide hydrolysis by altering the intrinsic

ATPase

activity

of

Hsp90

[17]. ATPase

homolog

1

(AHA1) then initiatesATP hydrolysis to produce the ener-

gy necessary to induce conformational changes essential to

client protein folding and release [17]. N-terminal Hsp90

Review

Corresponding author: Blagg, B.S.J. ([email protected]).

0165-6147/$ see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2011.11.001 Trends in Pharmacological Sciences, March 2012, Vol. 33, No. 3 129
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inhibitors

function

by

blocking

ATP-mediated

dimeriza-

tion

and

clamping

of

the

client

protein,

destabilizing

the

complex

and

prematurely

releasing

the

client

protein

[18].

Failure to produce mature client proteins is typically

cytotoxic

because

cellular

levels

can

decrease

following

ubiquitination,

and

proteasomal

degradation

of

improper-

ly folded proteins [17,18].

Chaperones are also essential

for

the refolding

of ag-gregated, damaged and denatured proteins. Under nor-

mal

conditions,

Hsp90 binds HSF1,

and this complex

prevents

the HSR

[19,20]. Upon

stress

or

heat shock,

Hsp90 releases HSF1 and ultimately induces the HSR

following phosphorylation,

trimerization and transloca-

tion into the nucleus [19,20]. The HSR is characterized, in

part, by the increased expression

of

Hsp27,Hsp40,Hsp70,

Hsp90 and other genes [19,20]. Pharmacologically, small-

molecule Hsp90 inhibitors mimic cellular stress by dis-

rupting

the Hsp90:HSF1 complex [21].

Therapeutically, the development

of

N-terminal

Hsp90

inhibitors may provide effective chemotherapeutic opportu-

nities because numerous

Hsp90

client proteins

are also

oncoproteins (e.g. Akt, ErbB2, BcrAbl, mutant p53 and

v-Src)

[12,13,22]. As

such,

inhibiting

Hsp90

is

an

attractive

target for cancer therapy because it simultaneously targets

multiple

molecular

components associatedwith all six

hall-

marks

of

cancer

[12,23]. However,

demonstrating

chemo-

therapeutic efficacy has been confounded by the narrow

therapeutic window

associated with these inhibitors

[13].

N-terminal

inhibitors,

such

as

thebenzoquinone ansamycin

antibiotics geldanamycin (GDA) and the structural analog

17-(allylamino)-17-demethoxy geldanamycin

(17-AAG)

(Figure 1), fail to

generate

therapeutic

windows

that disso-

ciate client protein

degradation

from HSR

induction [13].

Because

HSR

induction leads

to

Hsp70

and

Hsp90

over-

expression, these pro-survival Hsps antagonize the desired

endpoint of

cytotoxicity in

cancer

cells

by

increasing the

folding/refolding

of

the targeted

oncoproteins [1215,23].

Furthermore, both of thesecompounds exhibit hepatotoxic-

ity in

preclinical

(GDA)

or

clinical (17-AAG) trials

[13,15].OtherN-terminal inhibitors, such as celastrol, gedunin and

H2-gamendazole (Figure 1), also induce client protein deg-

radation

by

disrupting

the interfacebetweenHsp90

andthe

kinase co-chaperone Cdc37 (cell division cycle 37 homolog,

Saccharomycescerevisiae),but still suffer froman overlapin

concentrations that promote cytoprotective and cytotoxic

responses [24].

In contrast

to

selecting

for

cytoxicity,

it

has

been

pro-

posed that HSR induction can promote the disaggregation

of misfolded

proteins

associated

with

several

neurodegen-

erative

diseases.

In

this

regard,

N-terminal

inhibitors

decrease tau and Ab aggregation in AD, improve motor

function

in

spinal

and

bulbar

muscular

atrophy

and

pre-

ventmutant huntingtin (mHtt) aggregation inHD [2529].

However,

similar

to

cancer

therapies,

selecting

for

neuro-

protection still entails having a sufficient therapeutic win-

dow

to

minimize

potential

cytotoxicity.

This

can

be

accomplished

through

C-terminal

Hsp90

inhibition.

The C-terminus of Hsp90 contains an additional nucle-

otide-binding

domain

that

also

binds

the

natural

product

novobiocin

(Figure 1), a

DNA

gyrase

ATP

binding-site

inhibitor [30]. Although novobiocin itself is a poor inducer

of

client

protein

degradation

and

the

HSR,

higher

affinity

N-terminal

GDA: R = OMe17-AAG: R = NHCH2CHCH2

KU-32: R = CH3A4: R = H

C-terminal

Novobiocin

N-terminal Chemical HSR inducer

Celastrol Gedunin H2-Gamendazole HSF1A

R

O

O

O

O

O

O

O

O O

O

O

R

O

O

O

OO

O

O

OH

HO

OH

O

OO

O

O

OH

S

S

CI

CI

OOO

O

O

OH

OH

OH

OH

HN

HN

HO

OH

OMe

NH

NHN

N

N

N

H2N

NH2

CF3

MeO

MeO MeO

TRENDS in Pharmacological Sciences

Figure 1.

Structures of N-terminal Hsp90 inhibitors (GDA, 17-AAG, Celastrol, Gedunin, and H2-Gamendazole), C-terminal Hsp90 inhibitors (KU-32 and A4), and chemical

HSR inducer HSF1A.

Review Trends in Pharmacological Sciences March 2012, Vol. 33, No. 3

130


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and

more

potent

C-terminal

Hsp90

inhibitors

have

been

developed

around

the

coumarin

scaffold

of

novobiocin

[30,31]. Through

structureactivity

relationship

studies,

induction of the HSR and associated cytoprotection have

been

divested

from

client

protein

degradation

and

cytotox-

icity,

thus

expanding

the

dose

range

for

neuroprotection.

Representative examples are A4 and KU-32 [N-(7-

((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tet-rahydro-2H-pyran-2-yloxy)-2-oxo-2-methyl-chromen-3-

yl)acetamide]

(Figure

1), which

protects

against

Ab-in-

duced

death

of

cortical

neurons,

glucose-induced

cell

death

of unmyelinated sensory neurons and agonist-induced de-

myelination

of

myelinated

sensory

neurons

[3234].

More-

over, KU-32 has proved to be effective at reversing sensory

hypoalgesia

and

nerve

conduction

deficits

associated

with

DPN

in

streptozotocin

(STZ)-induced

type

1

diabetic

mice

without any overt cytotoxicity [34].

Chemical

induction

of

the

HSR

can

also

be

achieved

independently

of

Hsp90

inhibition.

For

example,

HSF1A

(Figure 1) induces the HSR through apparent interactions

with

the

chaperonin

TRiC

[TCP1

(tailless

complex

poly-

peptide 1)-ring complex] independently of Hsp90 binding[35]. In

NG108-15

neuroprogenitor

cells,

riluzole

(used

to

treat amyotrophic lateral sclerosis, ALS) administration

slows

HSF1

turnover

while

amplifying

HSF1

and

gluta-

mate

transporter

(GLT1)

expression/activation

[36]. GLT1

enhances glutamate recovery from the synaptic cleft, re-

ducing

the

likelihood

of

glutamate

excitotoxicity

(implicat-

ed

in

painful

diabetic

neuropathy,

ALS,

AD,

PD

and

HD)

[36]. However, the specific mechanisms underlying HSR

induction

by

HSF1A

and

riluzole

remain

undetermined

[35,36]. By

contrast,

compounds

such

as

quercetin

can

disrupt the DNA:HSF1 binding interface, preventing the

transcription

of

Hsp

mRNA

(especially

Hsp70)

[37].

HSF1also

regulates

several

genes

in

the

absence

of

heatshock.

For

example,

downregulating

HSF1

in HeLa

cervi-

cal carcinoma cells with small interfering RNA (siRNA)

modulated

the

expression

of

378

genes

involved

in

cell

cycle

regulation

and

cell

proliferation

[38]. This

suggests

that

HSF1 maintains the expression of several proteins re-

quired

for

survival

under

stressful

(i.e.

cancerous)

condi-

tions

in

addition

to

heat-shock-inducible

Hsps

[20,38].

Under non-oncogenic conditions, HSF1 cooperates with

NFATC2

(nuclear

factor

of

activated

T-cells-2)

to

regulate

the expression of aB-crystallin (small heat shock protein)

and the scaffolding protein PDZK3 [PSD-95/Dlg-A/ZO-1

(PDZ) domain-containing-3] [39]. This enables aB-crystal-

lin-mediated

disaggregation

of

mutant

huntingtin

in

R6/2

HD

mice

[39]. In

the

insulin-like

signaling

pathway

of

Caenorhabditis elegans, the FoxO (forkhead box other)

family

transcription

factor

DAF-16

(abnormal

dauer

for-

mation-16)

collaborates

with

HSF1

to

induce

the

expres-

sion of genes that increase life expectancy [19]. Hence,

HSF1

activation

enhances

cell

survival

under

both

normal

and

stressed

conditions.

Hsp70, Hsp40 and Hsp27

Independently

of

Hsp90,

Hsp70

and

Hsp40

form

hetero-

protein

complexes

that

offer

additional

neuroprotective

attributes. J-domain-containing proteins (J proteins),

such

as

Hsp40

and

CSPa

(cysteine

string

protein

a), bind

constitutive

Hsc70

(heat

shock

cognate

70)

and

inducible

Hsp70

(Hsp72)

to

enhance

the

ATPase

activity

of

Hsp70

[40]. Although

binding

affinities

differ

among

Hsp70

iso-

forms, there is a degree of interchangeabilitywith assorted

J

proteins

[40]. Specialized

neuronal

J

protein:Hsp70

interactions

repair

damaged

synaptic

vesicle

components,

enable vesicular secretion/reuptake (e.g. calcium channel

regulation,

clathrin

exchange),

permit

guanine

nucleotideexchange factor activities (e.g. CSPa) associated with G-

protein-coupled

receptors,

solubilize

potentially

toxic

aggregates

and

assist

in protein

ubiquitination

[40].

Hsp70 andHsc70 interactwithBAG-1 (Bcl-2-associated

athanogene)

and

CHIP

(C-terminus

of

Hsc70/Hsp70-inter-

acting protein) to flag irreparable proteins with ubiquitin

for

proteasomal

degradation

[41]. Alternatively,

BAG-2

enables

ubiquitin-independent

Hsp70-mediated

delivery

of irreparable substrates directly to 20S proteasomes for

degradation

[42]. Upon

Hsp70/BAG-2

saturation,

clear-

ance

duties

are

reinforced

by

the

Hsp70/BAG-1/CHIP

com-

plex [42]. Such triage management has been implicated in

tau clearance

(AD),

where

effective

Hsp70

chaperoning

becomes exhausted [42]. These data support that targetingselect

Hsp70

isoforms

via

chemical

modulators

may

en-

hance desired neuronal J protein interactions and disrupt

unfavorable

associations

(e.g.

tau

triage),

collectively

im-

proving

neuronal

function

[37,43]. Although

selective

inhi-

bition of Hsp70 isoforms provides promise as

neuroprotective

and

anti-cancer

therapeutics,

characteri-

zation

of

isoform

selective

scaffolds

that

modulate

Hsp70

(e.g. dihydropyrimidines, polyamines andATPmimics) are

still

underway

[37,43].

Insulin and IGF systems

To assess

the

importance

of

Hsps

within

the

insulin/IGF

signaling

cascades,

ligand

bioavailability,

receptor

locali-zation

and

signaling

components

are

reviewed

below.

In-

sulin bioavailability within the periphery depends upon

secretion

from

pancreatic

b

cells

in

the

islets

of

Langer-

hans.

Brain

insulin

levels

rely

upon

endothelial

facilitated

transport across the bloodbrain barrier (BBB) into the

cerebrospinal

fluid

(CSF).

These

levels

are

regulated

inde-

pendently

of

plasma

insulin

fluctuations

(e.g.

postprandial

insulin secretion) [44]. Under acute hyperinsulinemia,

insulin

translocation

is

limited

by

endothelial

saturation,

whereas chronic hyperinsulinemia (e.g. insulin resistance)

results in receptor internalization [45]. Mammalian brain

neurons can also endogenously synthesize small amounts

of

insulin

to

sustain

homeostatic

activities

[46].

IGF-I

and

IGF-II

are

abundantly

expressed

in

develop-

ing brains. In adults, endogenous IGF-I is diminished and

the

brain

relies

primarily

on

circulating

IGF-I

[47]. Upon

crossing

the

BBB,

IGF-I

can

modulate

neuronal

growth

and angiogenesis [47]. IGF-II is more highly expressed in

adult

brain

(especially

the

hippocampus),

but

its

produc-

tion

slowly

declines

with

age

[48]. In

the

periphery,

IGF-I

and IGF-II signaling supports both motor and sensory

nerve

viability

and

governs

neuronal

migration

and

neur-

itogenesis,

enabling

target

tissue

innervation

during

de-

velopment

and

nerve

regeneration

as

an

adult

[7].

IGF-I

is

localized to the ventral horn, dorsal root and sympathetic

ganglia,

Schwann

cells

and

target

tissues

(e.g.

skeletal


131


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muscle)

[7]. Schwann

cells

and

skeletal

muscle

also

provide

IGF-II for neurotrophic support [7].

Insulin receptor (IR) and IGF-I receptor (IGF-IR)expression

The

distribution

patterns

of

the

IR

and

IGF-IR

are

distinct

within

the

mammalian

nervous

system

and

correlate

with

several

areas

implicated

in

AD,

PD,

HD

and

DPN

(Table 1)

[7,49,50]. Structurally, IR and IGF-IR are tetrameric pro-

teins

consisting

of

two

extracellular

ligand-binding

domains

(a subunits)

and

two

receptor

tyrosine

kinase

(RTK) domains (b subunits) [5]. Interestingly, molecular

differences

between

receptor

compositions

can

affect

li-

gand

binding

affinities,

and

in

adipose,

muscle

and

liver

the metabolic effects of insulin are enhanced through

augmented

expression

of

the

IR-B

isoform

over

the

IR-A

isoform

[5].

Disruption

of

relative

IR-B:IR-A

expressionlevels

in

these

tissues

is

hypothesized

to

contribute

to

insulin resistance associated with type 2 diabetes [5].

IR-A

is

the

main

insulin

receptor

isoform

in nerves

and

exhibits

higher

binding

affinity

for

insulin,

IGF-I

and IGF-II compared to IR-B (Table 2 for IC50 values)

[5,51,52].

IGF-I/II

binding

to

IR-A

(and

IGF-IR)

selectively

induces

mitogenic

effects

via

the

MAPK/ERK

(mitogen-

activated protein kinase/extracellular-signal-regulated ki-

nase)

signaling

pathway,

suggesting

an

element

for

differ-

ential activation [5]. However, the effects elicited through

insulin binding to IR-A are not typically metabolic, as seen

with IR-B, but enhance viability and regulate biological

functions

such

as

synaptic

transmission

and

plasticity

[5].

IR and IGF-IR signaling

Ligand-induced IR/IGF-IR

autophosphorylation

enables its

RTK

domain

to

phosphorylate key

regulatory substrates

[e.g.

IRS-1

(insulin

receptor

substrate-1), IRS-2

or

Shc

(Src homology 2 domain-containing)] that activate the

MAPK/ERK,

mTOR/raptor (mammalian target

of

rapamy-

cin/regulatory-associated protein of mTOR) and PI3K(phosphatidylinositol 3-kinase) pathways

(Figure

2) [5].

Induction

of

the MAPK/ERK

pathway

via

receptor-

activated Ras

or

Rheb (brain isoform)

favorably enhances

transcription

factors

thatpromote

cellgrowth, proliferation

and survival (e.g. c-Fos and c-Myc) [5]. Ras/Rheb also

enhances mTOR/raptor

signaling,

stimulating p70S6

ki-

nase-

and eIF4E

(eukaryotic

translation

initiation factor

4E)-regulated cell growth, autophagy, metabolism, ribo-

some

biogenesis and translation

[5].

PI3K

pathway

induc-

tion synergistically enhances MAPK/ERK

and mTOR/

raptor signalingviaAkt (protein kinase B) phosphorylation

[5].

ActivatedAkt

phosphorylates TSC2 (tuberous sclerosis

complex2)

andpreventsGTP

hydrolysis

by

boundRas/Rheb[5].

Furthermore,

Akt-mediated

MDM2 (murine double

minute-2) phosphorylation enables p53 sequestration and

ubiquitination, consequently

reducing the expression of

TSC2,

IGF-binding protein-3

(prevents

IGF

binding to

IGF-IR) and PTEN [phosphatase and tensin homolog;

dephosphorylates

PIP3(phosphatidylinositol 3,4,5-triphos-

phate)] [53].

The importance of Akt in cell function and viability is

far-reaching

and

impacts

non-neuronal

and

neuronal

func-

tion and viability. For example, within the periphery, Akt

enhances GLUT4 (glucose transporter 4) vesicle transit

velocity and membrane docking/integration required for

glucose

transport

into

IR-B-expressing

tissues,

thereby

increasing

postprandial

glucose

clearance

[54]. Interest-

ingly, GLUT4 also localizes within several IR-expressing

regions

of

the

brain

(i.e.

cerebellum,

sensorimotor

cortex,

hippocampus,

pituitary

and

hypothalamus),

suggesting

a

metabolic role for insulin [49]. Akt also mitigates pro-

apoptotic

signaling

by

flagging

the

FoxO3a

(forkhead

box other

3a)

transcription

factor

for

ubiquitination,

re-

ducing Fas ligand stimulation of the extracellular death-

receptor

pathway

[5]. Akt-driven

BAD

phosphorylation

disrupts

BAD

tetramerization,

preventing

mitochondrial

permeabilization

and

initiation

of

the

mitochondrial

death

pathway [5]. Lastly, Akt phosphorylates and suppresses

GSK-3b

(glycogen

synthase

kinase-3b),

which

further

Table

1.

IR

and

IGF-IR

distribution

patterns

within

the

nervous

system

Receptor Central nervous system Refs Peripheral nervous system Refs

IR Cerebral cortex [49] Sensory neurons [7]

Hippocampus Sympathetic neurons

Amygdala

Striatum

Substantia nigra

Hypothalamus

Thalamus

Cerebellum

Pons

Medulla

Cervical spinal cord

IGF-IRa Hippocampus (adult) [7,50] Motor neurons [7,50]

Amygdala (adult) Sensory neurons

Parahippocampal gyrus (adult) Schwann cells

aUbiquitously expressed throughout most tissues, but most concentrated in the regions listed.

Table 2. Insulin, IGF-I and IGF-II IC50 (nM) valuesa

Isoform Ligand (IC50, nM) Ref.

IR-Ab Insulin (0.2) < IGF-II (2.2) < IGF-I (9.0) [51]

IR-B Insulin (0.5) < IGF-II (10.0) < IGF-I (90.0) [51]

IGF-IR IGF-I (0.8) < IGF-II (4.4) < Insulin (>100) [52]

aAdapted from Belfiore et al. [5].

bReceptor lacks exon 11, enhancing ligand binding affinity.


132


5/9

P

I

P

P

I

PP P

RTKtransphosphorylation

IRS-1/2

Shc

Grb2SoS

Ras

GDP

Ras

GTP

MEK1

ERK-1/2

c-Fos

c-Myc

Cell proliferationpro-survival transcription and translation

Raf-1

P P P PI3K

PIP3PIP3PIP2

TSC2

TSC1

p70S6K

4EBP1

eIF4E

4EBP1

eIF4E

P

P

P

P

P

P

P P

+

MDM2 P

p53

PTEN

GSK-3eIF2B PeIF2 PMet-tRNAiMet +

BAX P

CREB PTau P n

GLUT4vesicle

Pancreatic -islet cells

Insulin vesicles

Adipose, muscle and livercerebellum, sensorimotorcortices, hippocampus,pituitary, hypothalamus

Neurotransmission

Synaptic plasticity

Transmitter releaseand reuptake

BAD P

Cytochrome Crelease

FoxO3a P

Fas

(active)

Inhibits

Cell cycle arrest,autophagy and apoptosis

Plasma membrane

Key:

IGF-IR

Hsp90 client

PDK1

PDK1

Akt P

mTOR

Raptor

GSK-3 P

(inactive)

IR

ERK-1 P

GSK-3

HSF1

PHSF1

PHSF1

P

HSR

(active)

Hsp27

(aggregate)

Hsp27

(functional)

PKC

Akt P

P

I

Insulin IGF-I/II

I

IIor

MAPK

/ERKpathway

mTOR/Raptorpathw

ay

PI3Kpathway

Membranedocking/integ

ration

PKC P

Attenuated path

Induces

TRENDS in Pharmacological Sciences

Figure 2.

Insulin, IGF-I and IGF-II binding to IR and IGF-IR. Ligand binding triggers receptor autophosphorylation and RTK activation, permitting IRS-1, IRS-2 or Shc

phosphorylation. Mitogenic signaling pursues via Grb2 activation of the GEF (guanine nucleotide exchange factor) SoS, enabling Ras/Rheb activation. Activated Ras/Rheb

initiates theMAPK/ERKpathway through Raf-1phosphorylation and enhancesmTOR/raptor signaling, collectively increasing cell growth, proliferation, protein expression

andviability. Induction of the PI3Kpathwayenhances metabolic insulineffects andmitigates pro-apoptoticand anti-mitogenic signaling. Hsp90 client proteinsare indicated

with a pink bar and serve crucial roles in regulating insulin/IGF signaling. Potential modulation effects of insulin/IGF signaling components upon Hsp expression and

functionare shown in the black box.Abbreviations: BAD,Bcl-2-associated death promoter; BAX,Bcl-2-associated X; 4EBP1, eIF4E bindingprotein-1; CREB, cAMP-response

element binding; eIF2, eukaryotic initiation factor 2; eIF4E, eukaryotic translation initiation factor-4E; ERK-1/2, extracellular-signal-regulated kinase-1/2; FoxO3a, forkhead

box other 3a; GLUT4, glucose transporter 4; Grb2, growth factor receptor-bound protein 2; GSK-3b, glycogen synthase kinase-3b; HSF1, heat shock factor-1; Hsp, heat

shock protein; HSR, heat shock response; IGF-IR, insulin-like growth factor-I receptor; IR, insulin receptor; IRS-1/2, insulin receptor substrate-1/2; MAPK, mitogen-activated

protein kinase;MEK1, MAPK/ERKkinase 1; Met-tRNAiMet, initiator methionyl-tRNA; mTOR, mammalian target of rapamycin; raptor, regulatory-associatedproteinof mTOR;

MDM2, murine double minute-2; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3,

phosphatidylinositol 3,4,5-triphosphate; PKC, protein kinase C; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; Shc, Src homology 2 domain-

containing; SoS, son of sevenless; TSC, tuberous sclerosis complex.


133


6/9

enhances

mitochondrial

permeabilization

through

BAX

phosphorylation

[55].

Signaling effects upon synaptic transmission and

plasticity

Although

insulin/IGF-I

signaling

offers

generalized

neu-

roprotection, this signaling can also modulate neuron-spe-

cific

synaptic

plasticity.

For

example,

insulin/IGF-Isignaling significantly modulates glutamate (N-methyl-

D-aspartic

acid,

NMDA)-induced

excitatory

signaling

within the

peripheral

and

central

nervous

systems.

In

painful neuropathy studies, STZ-induced diabetic rats

overexpress

and

activate

metabotropic

glutamate

recep-

tors (mGluR5), thereby amplifying afferent nociceptive

signaling

from

sensory

dorsal

root

ganglia

(DRG)

[56].

Lumbar

spinal

sections

from

STZ-induced

hyperalgesic

diabetic rats also exhibit amplified phosphorylation and

activation

of

the

NR1

subunit

of

the

NMDA

receptor

(NMDAR)

[57]. In

this

regard

it

is

currently

hypothesized

that NMDAR activation induces the MAPK/ERK pathway

and provides

an

ERK-dependent

positive

feedback

loop

that leads to NR1 phosphorylation [57]. However, thespecific

molecular

components

associated

with

this

phos-

phorylation remain unclear. Furthermore, GABAB(g-ami-

nobutyric

acid,

class

B)

receptor

expression

is

significantly

reduced

in the

lumbar

spinal

cords

of

STZ-induced

diabetic

rats, suggesting that GABAergic inhibitory signaling re-

quired

for

the

suppression

of

nociceptive

transmission

may

be

compromised

[58]. Collectively,

these

data

suggest

that

insulin deprivation in the development of diabetes can

induce

glutamatergic

sensitization,

thereby

contributing

to

neuropathic

pain.

In

hippocampal

neurons,

long-term

potentiation (LTP) of NMDAR activity is hypothesized to

facilitate

memory

formation

[59]. Insulin/IGF-I

signaling

enhances

NMDAR

integration

into

the

plasma

membraneand

induces

the

phosphorylation/activation

of

NR2A

and

NR2B subunits of NMDARs via protein kinase C (PKC)

activation

[59,60]. NR2A

and

NR2B

expression

is

down-

regulated

in AD,

decreasing

the

likelihood

of

NMDAR

potentiation [59]. Further, oligomeric Ab preferentially

activates

NR2A

over

NR2B,

generating

an

aberrantly

high

NR2A:NR2B

ratio

that

favors

long-term

depression

(LTD),

potentially antagonizing memory establishment [59,61].

Another

insulin-induced

alteration

to

synaptic

plastici-

ty is its effect upon the reuptake of norepinephrine, an

essential neurotransmitter within the sympathetic ner-

vous system that also impacts upon attention, mood and

memory

in the

brain.

Norepinephrine

reuptake

is

facili-

tated

via

presynaptic

norepinephrine

transporters.

These

transporters are significantly reduced in the lumbar spinal

cords

of

both

type

1

and

type

2

diabetic

rats

as

well

as

the

hippocampi

and

cervical

ganglia

of

type

1

diabetic

mice

[8,62], suggesting that insulin deprivation negatively reg-

ulates

noradrenergic

tone.

Thus,

in

addition

to

generalized

neuroprotective

attributes,

insulin/IGF

signaling

can

di-

rectly influence synaptic transmission.

Hsp

interdependency

with

insulin

and

IGF-I

signaling

Thestability,

solubility and signaling

capabilities

of

several

insulin/IGF-I signaling components dependupon Hsp inter-

actions. For example,

maturation of

the insulin

receptor

hinges

upon

Hsp90-mediated

trafficking

of

the pro-receptor

through the endoplasmic

reticulum

[63].

Mutations within

RTK domains

are common

in

patients

with

severe

insulin

resistance andHsp90 exports these dysfunctional receptors

to

the cytoplasm for

proteolytic

degradation

[9,11]. Addi-

tional Hsp90

client proteins

include IGF-IR,

IRS-2, phos-

phoinositide-dependent kinase-1, Akt, Raf-1, MEK-1

(MAPK/ERK

kinase

1), ERK-1,

PKC

and

GSK-3b [10,64

71]. Hsp90 also binds raptor to enhance mTOR signaling

[72].

Although pro-apoptotic

GSK-3b can be

reduced

with

Hsp90 inhibition,

the collateral damage

to

other

signaling

components negates any potential therapeutic value and

inhibition

actually worsens

disease pathology[73].

Alterations in insulin/IGF-I signaling also impact upon

Hsp

expression

and

function.

For

instance,

Hsp27

is

stored

in

an 800 kDa multimeric state. Akt and PKC assist in

the dynamic cycling of phosphorylation states required to

reduce

these

Hsp27

multimers

into

functional

oligomeric/

monomeric

species

[74]. Furthermore,

progressive

HSF1

phosphorylation by ERK-1 (Ser307) and then GSK-3b

(Ser303)

was

recently

thought

to

suppress

the

HSR

[75].

Although this phosphorylation is now known to be GSK-3b-independent

under

normal

conditions,

assorted

physi-

ological stresses may induce allosteric changes in HSF1

that

enable

GSK-3b-mediated

phosphorylation

at

Ser303

or

nearby

residues

[76]. These

data

suggest

that

an

inter-

dependent relationship exists between insulin/IGF-I sig-

naling

and

functional

Hsp

expression.

Pathological insulin and IGF-I signal disruption

Ligand and receptor depletionIn

patients

with

type

1

diabetes,

pancreatic

b

cells

and/or

circulating insulin are selectively targeted through im-

mune-mediated

elimination,

destroying

the

majority

of

systemic

insulin

supply.

Interestingly,

antibodies

againstHsp90

have

been

found

in

some

type

1

diabetic

patients,

suggesting that systemic deficiencies in Hsp90 may be

associated

with

the

development

of

diabetes

[77]. In

bac-

teria,

the

Hsp70

ortholog

DnaK

can

bind

three

different

regions of human proinsulin (but not mature insulin)

implicated

in

autoimmune

elimination

[78]. Thus,

the

depletion

of

Hsp70

may

unmask

and

increase

epitope

exposure/recognition by T cells, accelerating the patho-

physiological

progression

of type

1

diabetes

[78].

AD has been proposed as a type 3 diabetes [46]. In AD

patient brains, postmortem analyses of IR and IGF-IR

mRNA levels have demonstrated an eight- to tenfold de-

crease

in

hippocampal

and

hypothalamic

neurons

and

a

40%

IR/IGF-IR

mRNA

drop

in

the

prefrontal

cortex,

areas

implicated in AD pathology [46]. Substantial reductions in

the mRNA

of

insulin

(hippocampus:

fourfold;

hypothala-

mus: twofold),

IGF-I

(hypothalamus

and

prefrontal

cortex:

five-to sixfold), and IGF-II (hippocampus and hypothala-

mus: threefold)

were

also

observed

[46]. The

timeline

of

these

reductions

directly

corresponds

to

the

Braak

stages

of AD pathological progression [79]. Observed increases of

IGF-I

levels

within

the

serum

and

CSF

of

AD

patients

are

believed

to

be

attributed

to

glial

secretion

in

response

to

neurodegeneration

[80].

In PD, IR mRNA declines within the substantia nigra

pars

compacta, a

brain

area

implicated

in PD

pathology,


134


7/9

without

affecting

localized

insulin

levels

[49]. Although

IR/

IGF-IR

levels

are

not

altered

in

people

with

HD,

3350% of

these

patients

develop

abnormal

glucose

tolerance,

sug-

gestive of altered insulin efficacy [49].

Pathological disruption of signaling components and

Hsp intervention

Several

mutations

contributing

to

insulin

resistance

intype 2 diabetes (e.g.Akt-2 mutations) have been identified

[11].

Grote

and

coworkers

demonstrated

that

IRS-2

phos-

phorylation

at

Ser731

is

elevated

in

the

DRG

of

both

type

1

and type 2 diabetic mice, whereas phosphorylated Akt

decreased

[81]. Ser731

phosphorylation

is

believed

to

be

inhibitory and is thought to destabilize IRS-2:receptor

associations,

leading

to

IRS-2

degradation

and

diminished

signaling

(e.g.

in

adipose

and

muscle

tissue)

[81]. Type

2

diabetic mice also displayed impaired insulin-induced

neurite

outgrowth,

suggesting

a

potential

breakdown

in

insulin-associated

repair

mechanisms

[4,81]. Similarly,

chronic insulin treatment of isolated DRG neurons (mim-

icking

hyperinsulinemia)

reduced

insulin-stimulated

Akt

activation [82]. Collectively, these data suggest that pe-ripheral

neurons,

as

with

metabolic

tissues,

can

develop

insulin resistance that compromises neurotrophic support

and

may

contribute

to

the

development

of

DPN.

Wehave

shown that induction of Hsp70 via

the C-termi-

nal Hsp90 inhibitor KU-32 reversed several clinical indices

of DPN

without

increasing overall insulin levels [34].

Al-

though the mechanism

of

action of

KU-32 remains

under

investigation, it seems prudent to speculate that its elicited

effects may

involve

the reconstitution of

impaired insulin/

IGF signaling components

in an

Hsp70-dependent manner

[34]. As such, the co-administration of other traditional

diabetic

treatments (e.g. insulin and

insulin analogs,

secre-

tagogs,

metformin

or

thiazolidinediones)with

HSR

inducersmay synergistically improve

DPN.

However,

this synergy

may develop similar risks to those associatedwithmisman-

aged

insulin therapy

if the compound

is

a

potent

and

broad

inducer of

molecular chaperones. Additional limitations for

HSR induction may include enhanced tumorigenesis be-

cause

IGF-I signaling

and

Hsps

are

significantly

upregu-

lated

in

several

formsof

cancer [83].

However,

suchobstacles

may be circumvented by readjusting primary treatment

regimens

and

adjuvant

therapies

(diabetic and

other che-

motherapeutics) or developing Hsp90 inhibitors that pro-

mote a less robust HSR,which is an attribute ofKU-32 [34].

In AD models, treating cultured hippocampal neurons

with

Ab-derived

diffusible

ligand

(ADDL)

decreases

IR

expression

by

activating

CaMKII

(calcium

calmodulin-de-

pendent kinase II)- and CK2 (casein kinase II)-mediated

receptor

internalization

[84]. Inversely,

activation

of

IR

signaling

decreases

ADDL

binding

and

associated

oxida-

tive stress, an effect further amplified by the insulin-

sensitizer

rosiglitazone

[84]. Therefore,

negating

ADDL

neurotoxicity

probably

requires

functional

insulin

signal-

ing and does not rely upon competitive binding [84]. Clear-

ance of

Ab

from

the

brain

to

the

periphery

is

also

facilitated

through

IGF-I

administration,

which

induces

the

translo-

cation

of

albumin

and

transthyretin

carrier

proteins

[85].

Ab142 treatment of rat primary cortical neurons acti-

vates

GSK-3b, enhancing

tau

phosphorylation,

cytochrome

c release, caspase-3 activation and HSF1 depletion [86].

Selective

inhibition

of

GSK-3b

reverses

these

effects

in

a

dose-dependent

manner

[86]. Ab

also

activates

c-Jun

N-

terminal kinase (JNK), which phosphorylates and inhibits

IRS-1/2

[87]. Abnormally

high

JNK

levels

are

also

impli-

cated in the

development

of

insulin

resistance

[87]. Fur-

thermore, the pathological progression of tauopathy-prone

pR5 mice

is

significantly

enhanced

in

diabetic

(STZ-in-duced) pR5 mice versus control mice [88]. Tau hyperpho-

sphorylation

in

wild-type

diabetic

mice

is

comparatively

less

than

diabetic

pR5

mice,

suggesting

that

insulin

deple-

tion enhances, but does not initiate, tauopathy [89]. In

addition,

ERK-1/2

activation

suppresses

b-secretase

(BACE) expression in neuroblastoma cells, thereby reduc-

ing

Ab142production [90]. Phosphorylated ERK-1/2 levels

increase

with

AD

pathology,

suggesting

its

role

as

a

natu-

raldefensivemechanismagainst accumulatingAb142 [90].

These

studies

collectively

suggest

that

restoring

insulin/

IGF-I

signaling

can

reduce

the

expression

of

Ab142 and

hyperphosphorylation of tau that are implicated in AD

pathology.

Hsps not only enhance insulin/IGF-I signaling compo-nent

expression

and

function

but

also

directly

interact

with

Ab and tau to negate their pathological effects. For exam-

ple,

Hsp90,

Hsp70

and

Hsp40

bind

to

and

prevent

early

phases

of

Ab142 self-assembly in vitro [25]. C-terminal

Hsp90 inhibitors also preventAb2535-induced neurotoxic-

ity

in

SH-SY5Y

neuroblastoma

cells

[32,33]. BAG-1-

and

BAG-2-mediated

tau

degradation

is

also

enhanced

through

Hsp70 induction [42]. Although Hsp70 reduces JNK acti-

vation

in

sympathetic

neurons,

its

effects

upon

JNK

acti-

vation

within

AD

brains

remain

to

be

determined

[91]. As

such, endogenous upregulation of Hsps should prevent Ab

and tau-induced

neurotoxicity.

However,

proteomic

analy-

ses

of

AD

patient

hippocampi

have

revealed

only

modestincreases

in Hsp70

[92]. In

patients

with

mild

cognitive

impairment (MCI), Hsp70 and Hsp27 are elevated within

the

inferior

parietal

lobule

(IPL),

an

area

implicated

in

memory

retrieval

[93]. This

same

region

also

demonstrates

a 70% increase in Hsp70 carbonyl levels, suggesting that

oxidative

damage

of

Hsp70

may

antagonize

endogenous

upregulation

efforts

[94]. MEK1

oxidation

was

also

ob-

served, further indicating insulin signal disruption [94].

Histochemical

analyses

of

brains

from

rTg4510

AD

mice

indicates a substantial induction of Hsp70 and Hsp27 (but

not Hsp90) with age and pathological progression [95]. A

more intense and largerHsp70 band also accrues along the

same

timeline,

suggesting

covalent

modification

(perhaps

ubiquitination)

of

Hsp70

[95]. The

induction

of

Hsp27

(also

observed in the hippocampus and caudate putamen) sug-

gests

the

employment

of

contingent

clearance

mechanisms

to

mitigate

compromised

or

exhausted

Hsp70-mediated

avenues [42,95]. Therefore, pharmacological HSR induc-

tion

may

expedite

the

reinforcement

needed

to

negate

Ab-

induced insulin/IGF-I

signal

transduction

and

facilitate

aberrant protein clearance.

Concluding

remarks

In

summary,

insulin

and

IGF-I

signaling

are

essential

to

maintain neuronal viability and synaptic transmission.

Induction

of

the

pro-survival

HSR

enhances

numerous


135


8/9

insulin

and

IGF-I

signaling

components

and

synergistical-

ly

mitigates

numerous

disease-specific

aberrant

proteins

that

interfere

with

this

signaling.

The

development

of

non-

cytotoxic C-terminal Hsp90 inhibitors enables potentially

more

nuanced

exploitation

of

the

HSR.

Such

inhibitors

have

already

proved

to

be

effective

towards

treating

DPN

[34]. Insulin and IGF-I deficiencies provide an intercon-

necting

link

between

the

pathologies

of

DPN,

AD,

PD,

andHD. The pharmacological development of new HSR indu-

cers

may

provide

a

multifaceted

therapeutic

approach

for

treating

several

insulin-associated

neurodegenerative

dis-

orders.

AcknowledgmentsThis work was supported by grants from the Juvenile Diabetes Research

Foundation (R.T.D.) and the National institutes of Health (NS058847,

R.T.D.) (CA120458, B.S.J.B.).

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