General Information:

Id: 3,870
Diseases: Alzheimer disease - [OMIM]
Huntington disease - [OMIM]
Mammalia
review
Reference: Ma QL et al.(2012) PAK in Alzheimer disease, Huntington disease and X-linked mental retardation Cell Logist 2: 117-125 [PMID: 23162743]

Interaction Information:

Comment In neurodegenerative diseases such as Alzheimer disease (AD), both PAK1 and PAK3 are dysregulated.
Formal Description
Interaction-ID: 38916

affects_activity of

gene/protein

PAK3

Comment Specifically proximal to cognitive decline, cytoplasmic levels of actin-regulating Rho GTPase and PAK1 kinase are decreased in moderate to severe AD, while aberrant activation and translocation of PAK1 appears around the onset of cognitive deficits.
Formal Description
Interaction-ID: 38960

phenotype

cognitive impairment

decreases_quantity of

gene/protein

PAK1

in AD cytoplasm
Comment Specifically proximal to cognitive decline, cytoplasmic levels of actin-regulating Rho GTPase and PAK1 kinase are decreased in moderate to severe AD, while aberrant activation and translocation of PAK1 appears around the onset of cognitive deficits.
Formal Description
Interaction-ID: 38967

phenotype

cognitive impairment

cooccurs with

phenotype

decreased actin-regulating Rho GTPase level

in AD cytoplasm
Comment LIM kinase inactivates cofilin, contributing to cofilin pathology, while the activation of Rho-dependent kinase ROCK increases Abeta production in AD.
Formal Description
Interaction-ID: 38968

gene/protein

LIM domain kinase

decreases_activity of

gene/protein

CFL1

contributing to cofilin pathology
Drugbank entries Show/Hide entries for CFL1
Comment LIM kinase inactivates cofilin, contributing to cofilin pathology, while the activation of Rho-dependent kinase ROCK increases Abeta (42) production in AD.
Formal Description
Interaction-ID: 38969

gene/protein

ROCK

increases_quantity of

if ROCK is activated
Comment Abeta activation of fyn disrupts neuronal PAK1 and ROCK-mediated signaling, resulting in synaptic deficits.
Formal Description
Interaction-ID: 38970

gene/protein

Amyloid beta peptide

increases_activity of

gene/protein

FYN

disrupting neuronal PAK1 and ROCK-mediated signaling, resulting in synaptic deficits
Drugbank entries Show/Hide entries for FYN
Comment Reductions in Abeta-induced PAK1 by the anti-amyloid compound curcumin suppress synaptotoxicity.
Formal Description
Interaction-ID: 38971

drug/chemical compound

Curcumin

decreases_activity of

gene/protein

PAK1

Comment Huntington disease (HD) shows also dysregulation of PAKs. PAK1 modulates mutant huntingtin (muhtt) toxicity by enhancing huntingtin aggregation, and inhibition of PAK activity protects HD as well as fragile X syndrome (FXS) symptoms.
Formal Description
Interaction-ID: 38985

gene/protein

PAK1

affects_activity of

gene/protein

HTT

Comment Huntington disease (HD) shows also dysregulation of PAKs. PAK1 modulates mutant huntingtin toxicity by enhancing huntingtin aggregation, and inhibition of PAK activity protects HD as well as fragile X syndrome (FXS) symptoms.
Formal Description
Interaction-ID: 38986

gene/protein

PAK1

affects_activity of

Comment Proximal to cognitive decline, there is a selective loss of synapses, especially excitatory synapses and vulnerable neurons in networks required for learning and memory in AD. Synaptic loss is accelerated at early stages of AD clinical symptoms and is more closely related to cognitive deficits than neuronal loss or amyloid buildup.
Formal Description
Interaction-ID: 39316

decreases_quantity of

cellular component

excitatory synapse

Comment Soluble aggregated Abeta forms called beta-amyloid-derived oligomers (ADDLs) or Abeta oligomers, including dimers, trimers and dodecamers (12-mer or Abeta*56) are implicated in synaptic dysfunction and loss in AD patients and AD animal models.
Formal Description
Interaction-ID: 39319

affects_quantity of

Comment A loss of PAK1 and PAK3 in cytoplasm of AD brain specimens, as well as in AD animal and cellular models was reported. Suggesting PAKs might play crucial roles in dendritic spine/synapses loss and cognitive defects in AD.
Formal Description
Interaction-ID: 39330

decreases_quantity of

gene/protein

PAK1

in AD brain cytoplasm
Comment A loss of PAK1 and PAK3 in cytoplasm of AD brain specimens, as well as in AD animal and cellular models was reported. Suggesting PAKs might play crucial roles in dendritic spine/synapses loss and cognitive defects in AD.
Formal Description
Interaction-ID: 39333

decreases_quantity of

gene/protein

PAK3

in AD brain cytoplasm
Comment Cognitive decline has been directly linked to the synaptic dysfunction, especially to synapses, postsynaptic and dendritic spine loss in AD and mental retardation (MR) syndromes.
Formal Description
Interaction-ID: 39335

phenotype

synaptic dysfunction

increases_activity of

phenotype

cognitive impairment

in AD; in mental retardation (MR) syndromes
Comment Cognitive decline has been directly linked to the synaptic dysfunction, especially to synapses, postsynaptic and dendritic spine loss in AD and mental retardation (MR) syndromes. In AD, postsynaptic and dendritic spine defects are an early event in memory circuits and therefore spatiotemporally situated to play a critical role in cognitive deficits.
Formal Description
Interaction-ID: 39340

phenotype

dendritic spine loss

increases_activity of

phenotype

cognitive impairment

in AD; in mental retardation (MR) syndromes
Comment The auto-phosphorylated PAK1 at Ser 141, an index of activity, was reduced by 73% in AD temporal cortex.
Formal Description
Interaction-ID: 39342

increases_activity of

gene/protein

PAK1

at Ser 141
Comment The auto-phosphorylated PAK1 at Ser 141, an index of activity, was reduced by 73% in AD temporal cortex.
Formal Description
Interaction-ID: 39349

decreases_quantity of

protein modification

PAK1-phosSer141

in AD temporal cortex
Comment PAK1 showed aberrant activation in AD, and this activated PAK1 was translocated from cytoplasm to membrane, probably to granular structures in a complex with its activators, GTPases RAC/CDC42. Dys-regulation (hyperactivation) of PAK1 followed by a loss of soluble pPAK may play an important role in dendritic spine /synapse loss and cognitive defects in AD.
Formal Description
Interaction-ID: 39352

affects_activity of

gene/protein

PAK1

Comment Cytoplasmic phosphoPAK1 (pPAK) was significantly reduced in a triple transgenic mouse model of AD that develops both plaque and tangle pathology and this loss of pPAK, and cognitive deficits were improved by dietary docosahexaenoic acid (DHA).
Formal Description
Interaction-ID: 39359

decreases_quantity of

protein modification

PAK1-phos

in cytoplasm; in a triple transgenic mouse model of AD
Comment Cytoplasmic phosphoPAK1 (pPAK) was significantly reduced in a triple transgenic mouse model of AD that develops both plaque and tangle pathology and this loss of pPAK, and cognitive deficits were improved by dietary docosahexaenoic acid (DHA).
Formal Description
Interaction-ID: 39360

drug/chemical compound

Docosahexaenoic acid

decreases_activity of

phenotype

cognitive impairment

in cytoplasm; in a triple transgenic mouse model of AD
Comment Cytoplasmic phosphoPAK1 (pPAK) was significantly reduced in a triple transgenic mouse model of AD that develops both plaque and tangle pathology and this loss of pPAK, and cognitive deficits were improved by dietary docosahexaenoic acid (DHA).
Formal Description
Interaction-ID: 39363

drug/chemical compound

Docosahexaenoic acid

increases_quantity of

protein modification

PAK1-phos

in cytoplasm; in a triple transgenic mouse model of AD
Comment Pathologic intracellular inclusion bodies (Hirano bodies) containing cofilin and smaller actin rods decorated by other actin-binding proteins are prominent features in the hippocampus and cortex of AD brains.
Formal Description
Interaction-ID: 39367

cooccurs with

phenotype

Hirano bodies

in the hippocampus and cortex of AD brains
Comment Pathologic intracellular inclusion bodies (Hirano bodies) containing cofilin and smaller actin rods decorated by other actin-binding proteins are prominent features in the hippocampus and cortex of AD brains.
Formal Description
Interaction-ID: 39377

gene/protein

CFL1

is localized in

phenotype

Hirano bodies

in the hippocampus and cortex of AD brains
Drugbank entries Show/Hide entries for CFL1
Comment Cofilin labeling in and around Abeta plaques is also observed in AD model APPswe transgenic mouse hippocampus.
Formal Description
Interaction-ID: 39389

gene/protein

CFL1

interacts (colocalizes) with

in hippocampus; of AD model APPswe transgenic mouse
Drugbank entries Show/Hide entries for CFL1
Comment Fibrillar Abeta 42 treatment of hippocampal neurons can activate PAK1, which in turn activates LIMK1 in vitro.
Formal Description
Interaction-ID: 39398

complex/PPI

Amyloid beta peptide (fibrillar)

increases_activity of

gene/protein

PAK1

in hippocampal neurons
Comment Abeta oligomers and fibrillar Abeta 42 treatment of hippocampal neurons can activate PAK1, which in turn activates LIMK1 in vitro.
Formal Description
Interaction-ID: 39408

gene/protein

PAK1

increases_activity of

gene/protein

LIMK1

in vitro
Comment Fibrillar Abeta could activate LIMK1 and induce ADF/cofilin phosphorylation in cultured neurons, suggesting LIM kinase is required for the neurotoxicity of Abeta.
Formal Description
Interaction-ID: 39417

complex/PPI

Amyloid beta peptide (fibrillar)

increases_activity of

gene/protein

LIMK1

in cultured neurons
Comment Fibrillar Abeta could activate LIMK1 and induce ADF/cofilin phosphorylation in cultured neurons, suggesting LIM kinase is required for the neurotoxicity of Abeta.
Formal Description
Interaction-ID: 39418

complex/PPI

Amyloid beta peptide (fibrillar)

increases_phosphorylation of

gene/protein

CFL1

in cultured neurons
Drugbank entries Show/Hide entries for CFL1
Comment Fibrillar Abeta could activate LIMK1 and induce ADF/cofilin phosphorylation in cultured neurons, suggesting LIM kinase is required for the neurotoxicity of Abeta.
Formal Description
Interaction-ID: 39419

complex/PPI

Amyloid beta peptide (fibrillar)

increases_phosphorylation of

gene/protein

DSTN

Drugbank entries Show/Hide entries for DSTN
Comment In AD brain, the number of pLIMK-positive neurons was significantly increased in those regions affected with AD pathology.
Formal Description
Interaction-ID: 39420

increases_quantity of

protein modification

LIMK1-phos

in AD brain neurons
Comment ROCKs can induce the processing of APP to the toxic Abeta (42) species and inhibitors of ROCKs, such as statins and certain NSAIDs (Non-steroid antiinflammatory drugs), can significantly suppress this amyloidogenic APP processing.
Formal Description
Interaction-ID: 39424

gene/protein

ROCK

increases_processing of

gene/protein

APP

and increases quantity of toxic Abeta (42)
Drugbank entries Show/Hide entries for APP
Comment ROCKs can induce the processing of APP to the toxic Abeta (42) species and inhibitors of ROCKs, such as statins and certain NSAIDs (Non-steroid antiinflammatory drugs), can significantly suppress this amyloidogenic APP processing.
Formal Description
Interaction-ID: 39434

drug/chemical compound

Statin

decreases_activity of

gene/protein

ROCK

Comment ROCKs can induce the processing of APP to the toxic Abeta (42) species and inhibitors of ROCKs, such as statins and certain NSAIDs (Non-steroid antiinflammatory drugs), can significantly suppress this amyloidogenic APP processing.
Formal Description
Interaction-ID: 39442

drug/chemical compound

NSAID

decreases_activity of

gene/protein

ROCK

Comment ROCKs can induce the processing of APP to the toxic Abeta (42) species and inhibitors of ROCKs, such as statins and certain NSAIDs (Non-steroid antiinflammatory drugs), can significantly suppress this amyloidogenic APP processing.
Formal Description
Interaction-ID: 39443

drug/chemical compound

Statin

decreases_quantity of

Comment ROCKs can induce the processing of APP to the toxic Abeta (42) species and inhibitors of ROCKs, such as statins and certain NSAIDs (Non-steroid antiinflammatory drugs), can significantly suppress this amyloidogenic APP processing.
Formal Description
Interaction-ID: 39444

drug/chemical compound

NSAID

decreases_quantity of

Comment One of the ROCK effectors, CRMP-2 (collapsin response mediator protein-2) displays a prominent hyperphosphorylation in AD, but CRMP-2 can also be phosphorylated by known tau kinases, GSK3B and Cdk5.
Formal Description
Interaction-ID: 39529

gene/protein

DPYSL2

affects_activity of

gene/protein

ROCK

Comment One of the ROCK effectors, CRMP-2 (collapsin response mediator protein-2) displays a prominent hyperphosphorylation in AD, but CRMP-2 can also be phosphorylated by known tau kinases, GSK3B and Cdk5.
Formal Description
Interaction-ID: 39530

increases_quantity of

protein modification

DPYSL2-hyperphos

Comment One of the ROCK effectors, CRMP-2 (collapsin response mediator protein-2) displays a prominent hyperphosphorylation in AD, but CRMP-2 can also be phosphorylated by known tau kinases, GSK3B and Cdk5.
Formal Description
Interaction-ID: 39531

gene/protein

GSK3B

increases_phosphorylation of

gene/protein

DPYSL2

Drugbank entries Show/Hide entries for GSK3B
Comment One of the ROCK effectors, CRMP-2 (collapsin response mediator protein-2) displays a prominent hyperphosphorylation in AD, but CRMP-2 can also be phosphorylated by known tau kinases, GSK3B and Cdk5.
Formal Description
Interaction-ID: 39532

gene/protein

CDK5

increases_phosphorylation of

gene/protein

DPYSL2

Drugbank entries Show/Hide entries for CDK5
Comment Abeta increases while a ROCK inhibitor prevents the RhoA-GTP response and CRMP-2 phosphorylation observed in cultured neuroblastoma cells. Hypothesis: Abeta increases the Rho GTPase activity via ROCK2 activation that enhances CRMP-2 phosphorylation to inhibit neurite outgrowth and synapse formation.
Formal Description
Interaction-ID: 39533

gene/protein

Amyloid beta peptide

increases_phosphorylation of

gene/protein

DPYSL2

in cultured neuroblastoma cells
Comment Both Abeta (oligomers and fibrillar amyloid) can activate ROCK and PAK1, which in turn activates LIMK1 and induces cofilin phosphorylation to mediate actin depolymerization.
Formal Description
Interaction-ID: 39534

gene/protein

ROCK

increases_activity of

gene/protein

LIMK1

Comment Both Abeta (oligomers and fibrillar amyloid) can activate ROCK and PAK1, which in turn activates LIMK1 and induces cofilin phosphorylation to mediate actin depolymerization.
Formal Description
Interaction-ID: 39535

increases_activity of

gene/protein

ROCK

Comment Both Abeta (oligomers and fibrillar amyloid) can activate ROCK and PAK1, which in turn activates LIMK1 and induces cofilin phosphorylation to mediate actin depolymerization.
Formal Description
Interaction-ID: 39536

protein modification

LIMK1-phos

increases_phosphorylation of

gene/protein

CFL1

Drugbank entries Show/Hide entries for CFL1
Comment Both Abeta (oligomers and fibrillar amyloid) can activate ROCK and PAK1, which in turn activates LIMK1 and induces cofilin phosphorylation to mediate actin depolymerization.
Formal Description
Interaction-ID: 39538

protein modification

CFL1-phos

increases_activity of

Comment NMDARs subunit NR2A and NR2B mRNA levels are decreased in hippocampus and entorhinal cortex from AD brains.
Formal Description
Interaction-ID: 39539

decreases_expression of

gene/protein

GRIN2A

in hippocampus and entorhinal cortex from AD brains
Drugbank entries Show/Hide entries for GRIN2A
Comment NMDARs subunit NR2A and NR2B mRNA levels are decreased in hippocampus and entorhinal cortex from AD brains.
Formal Description
Interaction-ID: 39540

decreases_expression of

gene/protein

GRIN2B

in hippocampus and entorhinal cortex from AD brains
Drugbank entries Show/Hide entries for GRIN2B
Comment Cofilin phosphatase called Slingshot (SSH), which antagonizes LIMK, blocks the neuro-cytotoxicity of fibrillar Abeta (42).
Formal Description
Interaction-ID: 39542

gene/protein

SSH

decreases_activity of

Comment IPA-3 is a potent PAK1 blocker.
Formal Description
Interaction-ID: 39544

drug/chemical compound

PAK1 inhibitor IPA-3

decreases_activity of

gene/protein

PAK1

Comment PF-3758309 is a PAK1 and PAK4 inhibitor.
Formal Description
Interaction-ID: 39545

drug/chemical compound

PAK4 inhibitor PF-3758309

decreases_activity of

gene/protein

PAK4

Comment Berberine chloride, which has been shown to ameliorate spatial memory impairment in a rat Abeta infusion model of AD, is a natural PAK1 blocker.
Formal Description
Interaction-ID: 39546

drug/chemical compound

Berberine chloride

decreases_activity of

gene/protein

PAK1

Comment PF-3758309 is a PAK1 and PAK4 inhibitor.
Formal Description
Interaction-ID: 39548

drug/chemical compound

PAK1 inhibitor PF-3758309

decreases_activity of

gene/protein

PAK1

Comment Berberine chloride, which has been shown to ameliorate spatial memory impairment in a rat Abeta infusion model of AD, is a natural PAK1 blocker.
Formal Description
Interaction-ID: 39563

drug/chemical compound

Berberine chloride

affects_activity of

The spatial memory impairment in a rat Abeta infusion model of AD is ameliorated by Berberine chloride.
Comment HD is caused by an expanded CAG repeat encoding a polyglutamine (polyQ expansion) tract in exon 1 of the HD gene Htt coding for huntingtin (htt). Normal HD alleles have 37 or fewer glutamines in this polymorphic tract, more than 37 of these residues cause HD. The length of the CAG tract is directly correlated with disease onset, with longer expansions leading to earlier onset of HD.
Formal Description
Interaction-ID: 39565

gene/protein mutant

HTT- (CAG-repeat expansion)

increases_activity of

HD is caused by an expanded CAG repeat encoding a polyglutamine (polyQ expansion) tract in exon 1 of huntingtin.
Comment Wild type huntingtin prevents PAK2 cleavage by caspase-3 and caspase-8, which activate PAK2 by releasing a constitutively active C-terminal kinase domain that mediates cell death.
Formal Description
Interaction-ID: 39567

gene/protein

HTT

decreases_processing of

gene/protein

PAK2

by caspase-3 and caspase-8
Comment PAK1 co-localized with muhtt (mutant huntingtin) aggregates in cell models and in human HD brains.
Formal Description
Interaction-ID: 39568

gene/protein

PAK1

interacts (colocalizes) with

gene/protein mutant

HTT-mut

in cell models and in human HD brains
Comment PAK1 overexpression enhanced the aggregation of muhtt (mutant huntingtin). This suggests that PAK1 plays a key role in enhancing htt-htt-interactions in a way that synergizes with the effects of the 'sticky' expanded polyQ tract to enhance aggregated muhtt toxicity.
Formal Description
Interaction-ID: 39569

gene/protein mutant

HTT-mut

interacts (colocalizes) with

gene/protein mutant

HTT-mut

if PAK1 is overexpressed
Comment PAK1 overexpression not only enhanced the aggregation of muhtt (mutant huntingtin), but also promotes soluble wild-type htt (wthtt)-wthtt, wthtt-muhtt and muhtt-muhtt interactions.
Formal Description
Interaction-ID: 39571

gene/protein

HTT

interacts (colocalizes) with

gene/protein mutant

HTT-mut

if PAK1 is overexpressed
Comment PAK1 overexpression not only enhanced the aggregation of muhtt (mutant huntingtin), but also promotes soluble wild-type htt (wthtt)-wthtt, wthtt-muhtt and muhtt-muhtt interactions.
Formal Description
Interaction-ID: 39572

gene/protein

HTT

interacts (colocalizes) with

gene/protein

HTT

If PAK1 is overexpressed, it enhances HTT-dimerization and -aggregation.
Comment The PAK-interacting exchange factor (alphaPIX/Cool2) was also identified as a novel htt interacting protein.
Formal Description
Interaction-ID: 39603

gene/protein

ARHGEF6

interacts (colocalizes) with

gene/protein

HTT

via N-terminal region of wtHTT
Comment Cool2/alphaPIX binds to both the N-terminal region of wthtt and muthtt, and colocalizes with muthtt in cells where it accumulates in the muthtt aggregates. Overexpression of alphaPIX enhanced muthtt aggregation by inducing SDS-soluble muthtt-muthtt interactions.
Formal Description
Interaction-ID: 39604

gene/protein

ARHGEF6

interacts (colocalizes) with

gene/protein mutant

HTT-mut

via N-terminal region of muthtt
Comment Both Abeta (oligomers and fibrillar amyloid) can activate ROCK and PAK1, which in turn activates LIMK1 and induces cofilin phosphorylation to mediate actin depolymerization.
Formal Description
Interaction-ID: 58397

complex/PPI

Amyloid beta peptide (oligomer)

increases_activity of

gene/protein

PAK1

Comment Both Abeta (oligomers and fibrillar amyloid) can activate ROCK and PAK1, which in turn activates LIMK1 and induces cofilin phosphorylation to mediate actin depolymerization.
Formal Description
Interaction-ID: 58398

complex/PPI

Amyloid beta peptide (fibrillar)

increases_activity of

gene/protein

ROCK

Comment Fibrillar Abeta 42 treatment of hippocampal neurons can activate PAK1, which in turn activates LIMK1 in vitro.
Formal Description
Interaction-ID: 80175

increases_activity of

gene/protein

PAK1

in hippocampal neurons
Comment Fibrillar Abeta could activate LIMK1 and induce ADF/cofilin phosphorylation in cultured neurons, suggesting LIM kinase is required for the neurotoxicity of Abeta.
Formal Description
Interaction-ID: 80176

increases_activity of

gene/protein

LIMK1

in cultured neurons
Comment Fibrillar Abeta could activate LIMK1 and induce ADF/cofilin phosphorylation in cultured neurons, suggesting LIM kinase is required for the neurotoxicity of Abeta.
Formal Description
Interaction-ID: 80177

increases_phosphorylation of

gene/protein

CFL1

in cultured neurons
Drugbank entries Show/Hide entries for CFL1
Comment Fibrillar Abeta could activate LIMK1 and induce ADF/cofilin phosphorylation in cultured neurons, suggesting LIM kinase is required for the neurotoxicity of Abeta.
Formal Description
Interaction-ID: 80178

increases_phosphorylation of

gene/protein

DSTN

Drugbank entries Show/Hide entries for DSTN
Comment Both Abeta (oligomers and fibrillar amyloid) can activate ROCK and PAK1, which in turn activates LIMK1 and induces cofilin phosphorylation to mediate actin depolymerization.
Formal Description
Interaction-ID: 80179

increases_activity of

gene/protein

ROCK

Comment The SRC family Tyr-kinase FYN phosphorylates NMDA receptor subunits NR2A and NR2B.
Formal Description
Interaction-ID: 81321

gene/protein

FYN

increases_phosphorylation of

gene/protein

GRIN2A

Drugbank entries Show/Hide entries for FYN or GRIN2A
Comment The SRC family Tyr-kinase FYN phosphorylates NMDA receptor subunits NR2A and NR2B.
Formal Description
Interaction-ID: 81322

gene/protein

FYN

increases_phosphorylation of

gene/protein

GRIN2B

Drugbank entries Show/Hide entries for FYN or GRIN2B