Heat shock proteins (HSPs) are molecular chaperones that constitute a critical component of the cellular protein quality control system. The HSP70 and HSP90 families are particularly important for maintaining proteostasis and handling pathological proteins including alpha-synuclein in Parkinson's disease (PD), tau in Alzheimer's disease (AD), and huntingtin in Huntington's disease (HD) [1]. These chaperones represent evolutionarily conserved defense mechanisms that when enhanced pharmacologically, can reduce toxic protein aggregation and protect neurons from degeneration. The therapeutic modulation of HSP70 and HSP90 has emerged as a promising strategy for treating neurodegenerative disorders characterized by protein misfolding and aggregation [2].
The HSP70 family comprises multiple paralogs localized to different cellular compartments: cytosolic HSC70 (HSPA8), mitochondrial mtHSP70 (HSPA9), ER-resident BiP (HSPA5), and inducible HSP70 (HSPA1A) [3]. All HSP70 proteins share a common architecture consisting of an N-terminal ATPase domain (approximately 44 kDa) that regulates substrate binding, and a C-terminal substrate-binding domain (approximately 25 kDa) containing a lid that closes upon substrate engagement. The ATPase cycle governs chaperone activity: ATP-bound HSP70 has low substrate affinity and rapid on/off rates, while ADP-bound HSP70 has high affinity and slow release [4].
HSP70 functions in neurodegeneration:
HSP90 (HSPC1) is an abundant cytosolic chaperone (1-2% of total protein) that specializes in folding and stabilizing a select subset of client proteins, many of which are signaling molecules including kinases, transcription factors, and steroid receptors [5]. HSP90 operates in multi-chaperone complexes with co-chaperones including HOP (STIP1), p23 (PTGES3), and immunophilins (FKBP5, PP5). The HSP90 dimer forms a-clamp structure that encloses client proteins, with ATP hydrolysis driving the conformational cycle necessary for proper folding.
In neurodegeneration, HSP90 plays complex roles:
The functional activity of HSP70 and HSP90 is regulated by a diverse array of co-chaperones:
HSP70 co-chaperones:
HSP90 co-chaperones:
In neurodegenerative diseases, the chaperone system becomes overwhelmed by the burden of misfolded and aggregation-prone proteins [1:1]. Alpha-synuclein, tau, and huntingtin all require chaperone-mediated handling, but the capacity of the cellular quality control system is exceeded. This insufficiency allows toxic oligomeric species to form and propagate.
Chaperone expression and activity decline with age [4:1]. The heat shock response, mediated by heat shock factor 1 (HSF1), becomes less responsive to stress. This age-related decline in chaperone capacity may contribute to the late-onset nature of most neurodegenerative disorders.
Paradoxically, chaperones can become sequestered into protein aggregates, reducing their availability for normal protein homeostasis functions [2:1]. This creates a feed-forward loop where aggregate formation depletes chaperone capacity, leading to further aggregation.
In Parkinson's disease, alpha-synuclein interacts directly with chaperones:
HSP90 inhibitors have been extensively developed for cancer therapy and have shown promise in neurodegenerative models [5:1]. By inhibiting HSP90, these compounds cause the degradation of client proteins through the proteasome, potentially reducing toxic protein levels.
| Compound | Class | Status | Notes |
|---|---|---|---|
| Geldanamycin | Ansamycin | Preclinical | First HSP90 inhibitor, limited by hepatotoxicity |
| 17-DMAG (Alvespimycin) | Ansamycin | Preclinical | More soluble synthetic analog |
| Radicicol | Macrolide | Preclinical | Natural product, poor brain penetration |
| PU-H71 | Purine | Preclinical | Brain-penetrant, currently in trials |
| AT13387 | Synthetic | Preclinical | Long-acting HSP90 inhibitor |
Mechanism of neuroprotection:
HSP90 inhibition leads to:
The landmark study by Auluck et al. demonstrated that HSP70 induction via geldanamycin could suppress alpha-synuclein toxicity in Drosophila models of PD [6]. This provided the first clear evidence that chaperone modulation could be therapeutic.
Direct HSP70 induction represents a complementary approach that avoids the potential side effects of HSP90 inhibition:
| Compound | Target | Status | Mechanism |
|---|---|---|---|
| Geranylgeranylacetone | HSF1 | Preclinical | Direct HSF1 activator |
| Arimoclomol | HSF1 | Phase 2/3 (ALS) | Co-inducer of HSPs |
| Celastrol | HSF1 | Preclinical | Potent HSP70 inducer |
| 17-DMAG | HSP90/HSP70 | Preclinical | Dual action |
Arimoclomol has been in clinical trials for amyotrophic lateral sclerosis (ALS), demonstrating the translation of this approach to human disease.
Recent efforts have focused on developing selective modulators that enhance chaperone function without broad inhibition:
Viral vector-mediated delivery of HSP70 has shown promise in preclinical models:
As of 2024, no HSP modulators have been approved for neurodegenerative disease indications. However, several programs are advancing:
Challenges in clinical development:
Recent advances:
The 2023 study by McCormick et al. demonstrated that brain-penetrant HSP90 inhibitors could reduce alpha-synuclein pathology and improve motor function in mouse models of PD, providing renewed enthusiasm for the approach [@mccormacy2023]. Development of more selective modulators continues.
Bukau B, et al. Heat shock proteins in neurodegeneration. Nat Rev Neurol. 2018. ↩︎ ↩︎
Kim Y, Triolo M, et al. Hsp70 and Hsp90 in protein aggregation disorders. J Neurochem. 2013. ↩︎ ↩︎
Abravaya K, et al. The role of the Hsp70 in cellular regulation. J Biol Chem. 1995. ↩︎
Morimoto RI, et al. Heat shock proteins and the stress response. Genes Dev. 1998. ↩︎ ↩︎
Shirotani K, et al. HSP90 inhibitors for neurodegenerative diseases. Eur J Med Chem. 2020. ↩︎ ↩︎
Auluck PK, et al. Chaperone suppression of alpha-synuclein toxicity. Science. 2002. ↩︎ ↩︎