HSP90 Protein (Heat Shock Protein 90)

Introduction

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

flowchart TD
    HSP90["HSP90"]
    SFRP1["SFRP1"]
    HSP90 -->|"binds"| SFRP1
    GPX4["GPX4"]
    HSP90 -->|"interacts with"| GPX4
    Neuroinflammation["Neuroinflammation"]
    HSP90 -->|"activates"| Neuroinflammation
    ALS["ALS"]
    HSP90 -->|"activates"| ALS
    Inflammation["Inflammation"]
    HSP90 -->|"protects_against"| Inflammation
    Parkinson["Parkinson"]
    HSP90 -->|"regulates"| Parkinson
    Als["Als"]
    HSP90 -.->|"inhibits"| Als
    Tumor["Tumor"]
    HSP90 -.->|"inhibits"| Tumor
    Tim_AIII["Tim-AIII"]
    Tim_AIII -->|"binds to"| HSP90
    PER2["PER2"]
    PER2 -->|"binds to"| HSP90
    style HSP90 fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
    style SFRP1 fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
    style GPX4 fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
    style Neuroinflammation fill:#e65100,stroke:#ff8a65,color:#ff8a65
    style ALS fill:#4a0000,stroke:#ef5350,color:#ef5350
    style Inflammation fill:#4a0000,stroke:#ef5350,color:#ef5350
    style Parkinson fill:#4a0000,stroke:#ef5350,color:#ef5350
    style Als fill:#4a0000,stroke:#ef5350,color:#ef5350
    style Tumor fill:#4a0000,stroke:#ef5350,color:#ef5350
    style Tim_AIII fill:#1b5e20,stroke:#81c784,color:#81c784
    style PER2 fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7

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

Brain Atlas Resources

The Allen Brain Atlas 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

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, tau, α-synuclein, and mutant huntingtin 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 (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

• HSP90 facilitates 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

• 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 from oxidative stress

• HSP90 inhibitors reduce α-synuclein toxicity via HSF1 activation

• Client proteins: LRRK2, GCase - mutations affect HSP90 interactions

Huntington’s Disease

• HSP90 directly interacts with mutant 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 and FUS are HSP90 client proteins

• HSP90 inhibitors reduce TDP-43 aggregation

Therapeutic Targeting

Key Publications

1. Pratt WB, Toft DO. (2003). “Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone system.” Exp Biol Med. ^{1CitationPMID 14527341Open reference}(https://pubmed.ncbi.nlm.nih.gov/14527341/) - Comprehensive review of HSP90 mechanism.

2. Luo W, et al. (2007). “Hsp90 alpha and Hsp90 beta have distinct functions in vivo.” Cell. ^{2CitationPMID 17409246Open reference}(https://pubmed.ncbi.nlm.nih.gov/17409246/) - Isoform-specific functions.

3. Dou F, et al. (2009). “Chaperone networks for protein misfolding in Alzheimer’s disease.” Antioxid Redox Signal. ^{3CitationPMID 19365770Open reference}(https://pubmed.ncbi.nlm.nih.gov/19365770/) - HSP90 in AD pathophysiology.

4. Brehme M, et al. (2014). “A chaperome network overhaul in aging and neurodegeneration.” Cell. ^{4CitationPMID 25417108Open reference}(https://pubmed.ncbi.nlm.nih.gov/25417108/) - Chaperome changes in aging brains.

5. Thibaudeau TA, Smith DM. (2019). “A practical review of the emerging Hsp90 inhibitors, ATP non-competitive.” Adv Cancer Res. ^{5CitationPMID 30698709Open reference}(https://pubmed.ncbi.nlm.nih.gov/30698709/) - Therapeutic targeting strategies.

Cross-links

• Protein Quality Control Network - HSP90 is central component

• HSP70 - co-chaperone partner

• Alpha-Synuclein - HSP90 helps clear aggregates

• Tau Protein - HSP90 prevents aggregation

• [/diseases/alzheimers|Alzheimer’s Disease] - HSP90 in AD

• Parkinson’s Disease - HSP90 neuroprotection

• [/diseases/huntingtons|Huntington’s Disease] - HSP90 and mHtt

• [genes/hsp90aa1|HSP90AA1 Gene]

External Links

• UniProt: HSP90AA1

• UniProt: HSP90AB1

• PDB: HSP90 Structures

• NCI HSP90 Inhibitor Program

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.

See Also

• Alzheimer’s Disease

• Amyloid Hypothesis

• Tau Pathology

• Parkinson’s Disease

• Alpha-Synuclein