HSP70 (Heat Shock Protein 70 / HSPA1A)

Pathway Diagram

flowchart TD
    HSP70["HSP70"]
    style HSP70 fill:#006494,stroke:#4fc3f7,stroke-width:3px,color:#e0e0e0
    Nf__b["Nf-Kb"]
    HSP70 -->|"regulates"| Nf__b
    Inflammation["Inflammation"]
    HSP70 -->|"activates"| Inflammation
    Als["Als"]
    HSP70 -->|"activates"| Als
    Amyotrophic_Lateral_Sclerosis["Amyotrophic Lateral Sclerosis"]
    HSP70 -->|"activates"| Amyotrophic_Lateral_Sclerosis
    Cancer["Cancer"]
    HSP70 -->|"regulates"| Cancer
    Apoptosis["Apoptosis"]
    HSP70 -->|"regulates"| Apoptosis
    poly_GA_aggregates["poly-GA aggregates"]
    HSP70 -->|"activates"| poly_GA_aggregates
    HSP70 -->|"therapeutic target"| Apoptosis
    NF__B["NF-KB"]
    NF__B -->|"regulates"| HSP70
    UBQLN2["UBQLN2"]
    UBQLN2 -->|"interacts with"| HSP70
    TIA1["TIA1"]
    TIA1 -->|"inhibits"| HSP70
    PI3K["PI3K"]
    PI3K -->|"regulates"| HSP70
    CANCER["CANCER"]
    CANCER -->|"regulates"| HSP70
    APOPTOSIS["APOPTOSIS"]
    APOPTOSIS -->|"regulates"| HSP70
    HIF["HIF"]
    HIF -->|"regulates"| HSP70
    style Nf__b fill:#5d4400,stroke:#ffd54f,color:#e0e0e0
    style Inflammation fill:#ef5350,stroke:#ef5350,color:#e0e0e0
    style Als fill:#ef5350,stroke:#ef5350,color:#e0e0e0
    style Amyotrophic_Lateral_Sclerosis fill:#ef5350,stroke:#ef5350,color:#e0e0e0
    style Cancer fill:#ef5350,stroke:#ef5350,color:#e0e0e0
    style Apoptosis fill:#5d4400,stroke:#ffd54f,color:#e0e0e0
    style poly_GA_aggregates fill:#006494,stroke:#888,color:#e0e0e0
    style NF__B fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style UBQLN2 fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style TIA1 fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style PI3K fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style CANCER fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style APOPTOSIS fill:#1b5e20,stroke:#81c784,color:#e0e0e0
    style HIF fill:#1b5e20,stroke:#81c784,color:#e0e0e0

Introduction

Hsp70 (Heat Shock Protein 70 Hspa1A) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Heat Shock Protein 70 (HSP70) is a 70 kDa ATP-dependent molecular chaperone and a central node of the cellular proteostasis network. The human HSP70 family comprises at least 13 members, with HSPA1A (the major inducible form, also called HSP72 or HSP70-1) and HSPA8 (the constitutive form, also called HSC70 or HSP73) being the most relevant to neurodegeneration. HSPA1A is encoded by the HSPA1A gene on chromosome 6p21.33, within the major histocompatibility complex (MHC) class III region (Saxena et al., 2025).

HSP70 proteins are among the most highly conserved proteins across all domains of life and perform essential functions in protein folding, disaggregation, translocation, and degradation. In the context of neurodegeneration, HSP70 directly opposes the fundamental disease mechanism of protein-aggregation — it binds to misfolded tau]/proteins/tau, [alpha-synuclein/proteins/[alpha-synuclein), tdp-43, huntingtin, and sod1-protein to prevent their aggregation, disaggregate existing fibrils, and facilitate clearance via the ubiquitin-proteasome-system and autophagy (Kampinga & Bhatt, 2016; Bohush et al., 2019).

The decline of the heat shock response (HSR) with aging — and the consequent failure of HSP70-mediated proteostasis — is increasingly recognized as a convergent mechanism underlying aging-associated neurodegeneration. Conversely, pharmacological induction of HSP70 expression represents one of the most promising therapeutic strategies against protein misfolding diseases (Kalmar & Greensmith, 2023).

Structure and Mechanism

Domain Architecture

HSP70 proteins share a conserved three-domain architecture (~640 amino acids):

1. N-terminal Nucleotide-Binding Domain (NBD) (~40 kDa, residues 1–385):

   • ATPase domain with two lobes (I and II) forming a deep nucleotide-binding cleft

   • ATP hydrolysis drives the conformational cycle that powers substrate binding and release

   • Structurally homologous to actin and hexokinase

2. Substrate-Binding Domain (SBD) (~15 kDa, residues 393–507):

   • β-sandwich subdomain (SBDβ) containing the substrate-binding cleft

   • Recognizes hydrophobic peptide segments of 5–7 residues enriched in leucine, isoleucine, valine, and phenylalanine

   • Exposed in non-native proteins but buried in properly folded structures

3. C-terminal α-Helical Lid (~10 kDa, residues 508–641):

   • Five α-helices that act as a “lid” over the substrate-binding cleft

   • Open in the ATP-bound state (fast substrate on/off) → Closed in the ADP-bound state (tight substrate binding)

   • Contains the EEVD motif at the extreme C-terminus that mediates co-chaperone interactions (e.g., with Hop/STIP1 and hsp90

Allosteric Chaperone Cycle

The HSP70 chaperone cycle is driven by ATP hydrolysis and regulated by co-chaperones:

1. Substrate delivery: J-domain proteins (JDPs, e.g., DNAJB1, DNAJA1) capture misfolded substrates and deliver them to the open, ATP-bound form of HSP70

2. Substrate trapping: JDP binding stimulates ATP hydrolysis → ADP-bound HSP70 closes the lid, trapping the substrate

3. Substrate processing: Nucleotide exchange factors (NEFs), particularly HSP110 (HSPH1) family members, catalyze ADP→ATP exchange

4. Substrate release: ATP binding reopens the lid, releasing the substrate for refolding, or directing it to degradation via the ubiquitin-proteasome-system (aided by co-chaperone CHIP/STUB1)

HSP70 vs. HSC70 (HSPA1A vs. HSPA8)

In aging and neurodegeneration, HSF1 (heat shock factor 1) — the master transcription factor controlling HSPA1A induction — becomes impaired, leading to an inadequate heat shock response and failure to upregulate HSP70 when most needed (Kalmar & Greensmith, 2023).

Normal Function

Protein Folding and Quality Control

HSP70 is the central hub of the protein quality control network:

• De novo folding: Assists co-translational and post-translational folding of ~15–20% of all newly synthesized proteins

• Refolding: Rescues stress-denatured proteins to their native state

• Disaggregation: Working with HSP110 and JDPs, the HSP70 disaggregation machinery can extract monomers from amyloid fibrils

• Triage decision: Directs irreversibly misfolded proteins to proteasomal or autophagic degradation via CHIP E3 ubiquitin ligase

• Membrane translocation: Facilitates protein import into mitochondrial-dynamics and the endoplasmic reticulum

Neuroprotective Functions

In neurons, HSP70 provides multiple layers of protection:

• Inhibits apoptosis by blocking caspase-9 activation at the apoptosome (prevents Apaf-1 oligomerization)

• Suppresses necroptosis and pyroptosis pathways

• Reduces oxidative-stress by stabilizing antioxidant enzymes

• Maintains synaptic protein homeostasis

Role in Disease

Alzheimer’s Disease

HSP70 directly counters the two hallmark pathologies of AD:

Tau: The HSP70/HSP90 multichaperone complex buffers pathological tau]/proteins/tau through extensive intermolecular contacts that depend on tau’s aggregation-prone repeat region (Nachman et al., 2022). HSP70 facilitates:

• Tau binding to microtubules — preventing its release and subsequent aggregation

• Degradation of hyperphosphorylated tau via CHIP-mediated ubiquitination

• The HSPA1A isoform has higher affinity for tau than the constitutive HSPA8 (Thompson et al., 2012)

amyloid-beta: HSP70 interacts with Amyloid-Beta oligomers and modulates their aggregation:

• Reduces amyloid-beta-induced synaptic toxicity by binding prefibrillar intermediates

• Cooperates with clusterin in extracellular protein quality control

Parkinson’s Disease

HSP70 is a critical suppressor of alpha-synuclein pathology:

• Fibril disaggregation: The HSC70/DnaJB1/Apg2 disaggregation machinery can completely reverse α-synuclein fibril aggregation, extracting monomer units directly from fibril ends (Gao et al., 2021)

• Oligomer blockade: HSP70 directly blocks α-synuclein oligomerization via a noncanonical interaction site in its C-terminal domain (Aprile et al., 2017)

• In vivo protection: Overexpression of HSP70 in α-synuclein transgenic mice significantly reduces high-molecular-weight and detergent-insoluble α (Klucken et al., 2004)

However, the disaggregation process can paradoxically generate spreading-competent toxic α-synuclein species — small oligomeric fragments released during HSP110-mediated disaggregation can serve as seeds for prion-like propagation (Tittelmeier et al., 2020). This dual nature complicates therapeutic strategies.

ALS and FTD

HSP70 plays a protective role against tdp-43-proteinopathy:

• HSP70 co-phase separates with tdp-43 in liquid-liquid-phase-separation condensates, maintaining them in a dynamic, liquid-like state and preventing pathological amyloid aggregation (Gu et al., 2021)

• HSP70 binds to the highly aggregation-prone transient α-helix of tdp-43 via its nucleotide-binding domain

• HSPA1A and co-chaperone DNAJB2a promote clearance of tdp-43 aggregates upon HSF1 activation

• In sod1-protein-ALS models, HSP70 overexpression delays disease onset and extends survival

Huntington’s Disease

• HSP70 suppresses polyglutamine aggregation by binding to expanded polyQ tracts in huntingtin

• Works cooperatively with HSP40 (DNAJB1) to maintain solubility of mutant huntingtin

• HSP70 upregulation reduces inclusion body formation and improves neuronal survival in HD models

Therapeutic Targeting

HSP70 Inducers (HSF1 Activators)

Pharmacological activation of the heat shock response to upregulate HSP70 expression:

Direct HSP70 Modulators

• YM-01 and JG-98: Allosteric modulators of HSP70 that shift the chaperone toward pro-degradation mode, enhancing clearance of tau via CHIP-mediated ubiquitination

• MKT-077: Rhodacyanine dye that binds the NBD and promotes tau degradation; analog JG-48 has improved pharmacokinetic properties

• SW02: HSP70 activator that enhances chaperone-mediated autophagy of α-synuclein

Gene Therapy

• AAV-mediated overexpression of HSPA1A or HSP110 in preclinical models provides neuroprotection

• Challenges include achieving sufficient expression levels in target brain regions and the narrow therapeutic window between protective disaggregation and release of toxic species

Background

The study of Hsp70 (Heat Shock Protein 70 Hspa1A) 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.