HSP90 Protein (Heat Shock Protein 90)

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HSP90 Protein (Heat Shock Protein 90)

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HSP90 Protein (Heat Shock Protein 90)

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HSP90 Protein (Heat Shock Protein 90)</th>
</tr>
<tr>
<td class="label">Approach</td>
<td>Agent/Strategy</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>Geldanamycin</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>17-AAG (Tanespimycin)</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>17-DMAG (Alvespimycin)</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>PU-H71</td>
</tr>
<tr>
<td class="label">HSP90 activators</td>
<td>Natural compounds</td>
</tr>
<tr>
<td class="label">Co-chaperone modulators</td>
<td>p23 inhibitors</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">107 edges</a></td>
</tr>
</table>

Hsp90 Protein (Heat Shock Protein 90) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Pathway Diagram

...

HSP90 Protein (Heat Shock Protein 90)

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HSP90 Protein (Heat Shock Protein 90)</th>
</tr>
<tr>
<td class="label">Approach</td>
<td>Agent/Strategy</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>Geldanamycin</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>17-AAG (Tanespimycin)</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>17-DMAG (Alvespimycin)</td>
</tr>
<tr>
<td class="label">HSP90 inhibitors</td>
<td>PU-H71</td>
</tr>
<tr>
<td class="label">HSP90 activators</td>
<td>Natural compounds</td>
</tr>
<tr>
<td class="label">Co-chaperone modulators</td>
<td>p23 inhibitors</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/fibrosis" style="color:#ef9a9a">Fibrosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">107 edges</a></td>
</tr>
</table>

Hsp90 Protein (Heat Shock Protein 90) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Pathway Diagram

Mermaid diagram (expand to render)

Knowledge graph relationships for HSP90 (315 total edges in KG)

Brain Atlas Resources

The [Allen Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=HSP90AA1) provides gene expression data for HSP90AA1:

Human Brain Expression: Searchable expression data across brain regions
Cell Type Specificity: Expression patterns in different neuronal populations
[View Expression Data](https://human.brain-map.org/microarray/search/show?search_term=HSP90AA1)

Overview

HSP90 (Heat Shock Protein 90) is a highly abundant molecular chaperone protein that constitutes 1-2% of total cellular protein. It plays a critical role in protein folding, stabilization, and quality control by assisting the refolding of misfolded proteins and preventing aggregation. HSP90 is particularly important in neurodegenerative diseases as it helps manage proteotoxic stress from misfolded [Aβ](/proteins/amyloid-beta), [tau](/proteins/tau), α-synuclein, and mutant [huntingtin](/genes/htt) proteins.

Structure

HSP90 is a dimeric protein with each monomer containing:

N-terminal ATPase domain (1-220 aa): Binds and hydrolyzes ATP; target of many small-molecule inhibitors
Middle domain (220-370 aa): Client protein binding site; contains catalytic loop for ATP hydrolysis
C-terminal dimerization domain (370-600 aa): Mediates homodimer formation; contains EEVD motif for co-chaperone binding

HSP90 isoforms:

[HSP90AA1](/proteins/hsp90aa1-protein) (HSP90α): Inducible form, predominantly in brain
HSP90AB1 (HSP90β): Constitutively expressed, major cytoplasmic form
GRP94 (ER-resident): HSP90 family member in endoplasmic reticulum
TRAP1 (mitochondrial): HSP90 in mitochondria

Normal Function

Protein Folding and Quality Control

HSP90 ATPase cycle: ATP binding → conformational change → client protein binding → ATP hydrolysis → client release
Folds ~10% of the proteome, including kinases, steroid receptors, and transcription factors
Works with co-chaperones (HSP70, HSP40, p23, CDC37) in the chaperone complex

Cellular Homeostasis

Maintains proteostasis under stress conditions (heat shock, oxidative stress)
Regulates signal transduction pathways via client proteins
Supports cell survival under proteotoxic stress
Involved in antigen presentation and immune function

Neurological Function

Critical for neuronal protein homeostasis
Supports synaptic function and plasticity
Protects against age-related proteostasis decline

Role in Disease

[Alzheimer's Disease](/diseases/alzheimers-disease)

HSP90 facilitates [tau](/proteins/tau) refolding and prevents tau aggregation
Levels of HSP90 decrease with age, correlating with Aβ accumulation
HSP90 overexpression reduces Aβ toxicity and improves memory
HSP90 inhibitors promote Aβ clearance via upregulated [autophagy](/entities/autophagy)
Therapeutic potential: HSP90 activators or co-chaperone modulators

Parkinson's Disease

HSP90α is neuroprotective in PD models
Helps refold and clear α-synuclein aggregates
Protects dopaminergic [neurons](/entities/neurons) from oxidative stress
HSP90 inhibitors reduce α-synuclein toxicity via HSF1 activation
Client proteins: LRRK2, GCase - mutations affect HSP90 interactions

[Huntington's Disease](/mechanisms/huntington-pathway)

HSP90 directly interacts with mutant [huntingtin](/proteins/huntingtin) (mHtt)
Facilitates folding of polyglutamine-expanded proteins
HSP90 inhibition promotes clearance of mHtt aggregates
Co-chaperone DNAJB6 more effective at preventing aggregation

Amyotrophic Lateral Sclerosis

Manages mutant SOD1 aggregation in familial ALS
[TDP-43](/mechanisms/tdp-43-proteinopathy) and FUS are HSP90 client proteins
HSP90 inhibitors reduce TDP-43 aggregation

Therapeutic Targeting

Key Publications

Pratt WB, Toft DO. (2003). "Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone system." Exp Biol Med. PMID: 14527341(https://pubmed.ncbi.nlm.nih.gov/14527341/) - Comprehensive review of HSP90 mechanism.

Luo W, et al. (2007). "Hsp90 alpha and Hsp90 beta have distinct functions in vivo." Cell. PMID: 17409246(https://pubmed.ncbi.nlm.nih.gov/17409246/) - Isoform-specific functions.

Dou F, et al. (2009). "Chaperone networks for protein misfolding in Alzheimer's disease." Antioxid Redox Signal. PMID: 19365770(https://pubmed.ncbi.nlm.nih.gov/19365770/) - HSP90 in AD pathophysiology.

Brehme M, et al. (2014). "A chaperome network overhaul in aging and neurodegeneration." Cell. PMID: 25417108(https://pubmed.ncbi.nlm.nih.gov/25417108/) - Chaperome changes in aging brains.

Thibaudeau TA, Smith DM. (2019). "A practical review of the emerging Hsp90 inhibitors, ATP non-competitive." Adv Cancer Res. PMID: 30698709(https://pubmed.ncbi.nlm.nih.gov/30698709/) - Therapeutic targeting strategies.

Cross-links

[Protein Quality Control Network](/mechanisms/protein-quality-control-network) - HSP90 is central component
[HSP70](/proteins/hsp70) - co-chaperone partner
[Alpha-Synuclein](/proteins/alpha-synuclein) - HSP90 helps clear aggregates
[Tau Protein](/proteins/tau) - HSP90 prevents aggregation
[/diseases/alzheimers|[Alzheimer's Disease](/diseases/alzheimers-disease)] - HSP90 in AD
[Parkinson's Disease](/diseases/parkinsons-disease-disease) - HSP90 neuroprotection
[/diseases/huntingtons|[Huntington's Disease](/mechanisms/huntington-pathway)] - HSP90 and mHtt
[genes/hsp90aa1|[HSP90AA1](/proteins/hsp90aa1-protein) Gene]

External Links

[UniProt: HSP90AA1](https://www.uniprot.org/P07900)
[UniProt: HSP90AB1](https://www.uniprot.org/P08238)
[PDB: HSP90 Structures](https://www.ebi.ac.uk/pdbe/entry/pdb/2ioj)
[NCI HSP90 Inhibitor Program](https://www.cancer.gov/about-cancer/treatment/drugs/hsp90)

This page was created to expand protein coverage in NeuroWiki. Last updated: 2026-03-03

Background

The study of Hsp90 Protein (Heat Shock Protein 90) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[Zuo J, et al, HSP90 and neurodegenerative diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/25850067/)

[Lackie RE, et al, The HSP90 molecular chaperone network in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/31710195/)

[Luo W, et al, HSP90 inhibitors in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/32762761/)

[Taylor SE, et al, HSP90 and tauopathy (2021)](https://pubmed.ncbi.nlm.nih.gov/33497962/)

Pathway Diagram

The following diagram shows the key molecular relationships involving HSP90 Protein (Heat Shock Protein 90) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

HSP90

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slug	proteins-hsp90
kg_node_id	HSP90
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-88b92b55fc64
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-hsp90'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

100%

Debates

0

Incoming

55

Outgoing

73

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

HSP90 Protein (Heat Shock Protein 90)

HSP90 Protein (Heat Shock Protein 90)

Introduction

Pathway Diagram

HSP90 Protein (Heat Shock Protein 90)

Introduction

Pathway Diagram

Brain Atlas Resources

Overview

Structure

HSP90 isoforms:

Normal Function

Protein Folding and Quality Control

Cellular Homeostasis

Neurological Function

Role in Disease

[Alzheimer's Disease](/diseases/alzheimers-disease)

Parkinson's Disease

[Huntington's Disease](/mechanisms/huntington-pathway)

Amyotrophic Lateral Sclerosis

Therapeutic Targeting

Key Publications

Cross-links

External Links

Background

See Also

References

Pathway Diagram

💬 Discussion