Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases

Abstract

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion-based neurodegeneration are associated with the accumulation of misfolded proteins, resulting in neuronal dysfunction and cell death. However, current treatments for these diseases predominantly address disease symptoms, rather than the underlying protein misfolding and cell death, and are not able to halt or reverse the degenerative process. Studies in cell culture, fruitfly, worm and mouse models of protein misfolding-based neurodegenerative diseases indicate that enhancing the protein-folding capacity of cells, via elevated expression of chaperone proteins, has therapeutic potential. Here, we review advances in strategies to harness the power of the natural cellular protein-folding machinery through pharmacological activation of heat shock transcription factor 1--the master activator of chaperone protein gene expression--to treat neurodegenerative diseases.

Figure 1. Chaperone proteins and maintenance of protein homeostasis

Misfolding of disease-causing proteins results in the disruption of protein homeostasis when misfolded monomers accumulate and begin to form intermediate soluble oligomers or fibrils, and eventually form mature insoluble aggregates. Chaperone proteins assist in the correct folding of proteins and prevent the formation of toxic oligomeric species. Increasing the expression of chaperone proteins enhances the ability of cells to maintain protein homeostasis even in the presence of aggregation-prone proteins. It is not yet clear whether increased expression of chaperone proteins will prevent the formation of mature aggregates and promote their degradation.

Figure 2. HSF1 activation and attenuation cycle

In the absence of cellular stress, heat shock transcription factor 1 (HSF1) exists as an inactive monomer in the cytoplasm. Its activity is repressed via the interaction of the chaperone proteins heat shock protein 90 (HSP90), HSP70 and HSP40 as well as its phosphorylation on Ser303 and Ser307 residues. In response to proteotoxic stress HSP90 is thought to bind to misfolded proteins and dissociate from HSF1, thereby allowing HSF1 to form homotrimers and become localized to the nucleus to bind to heat shock elements in the promoters of stress-responsive genes. Disulphide bonding occurs between HSF1 monomers to stabilize trimer formation. HSP70 is known to associate with HSF1 even when it is bound to DNA, and it may continue to repress HSF1 until a secondary stimulus promotes its dissociation. Following DNA binding HSF1 is sumoylated — this is a repressive modification that is attenuated with prolonged heat stress. HSF1 is hyperphosphorylated on up to 12 serine residues during HSF1-dependent transactivation. HSF1-dependent transactivation is repressed via a negative feedback loop, in which HSP70 and HSP40 re-associate with the HSF1 transactivation domain, and HSF1 becomes dissociated from DNA following acetylation of Lys80 in its DNA binding domain. It remains unclear whether the disulphide-linked HSF1 trimers are dissociated into cytoplasmic monomers or whether they are degraded.

Figure 3. HSF1 regulation by post-translational modifications

In response to cellular stress, heat shock transcription factor 1 (HSF1) is hyperphosphorylated on up to 12 serine residues; this occurs in parallel with HSF1-dependent transactivation. Three sites of phosphorylation involved in HSF1 activation that have been studied in detail are shown. HSF1 activity is also repressed by constitutive phosphorylation of Ser303 and Ser307, and by stress-responsive sumoylation of Lys298 (represented on the figure as ‘Su’). The binding of HSF1 to DNA is inhibited by the acetylation of Lys80 (represented on the figure as ‘Ac’). AD, activation domain; DBD, DNA binding domain; LZ1, leucine zipper domain 1.

Figure 4. Proposed mechanisms to promote the direct activation of HSF1

We propose three potential approaches to promote the direct activation of heat shock transcription factor 1 (HSF1). a | First, a small molecule specifically designed to bind the interface between heat shock protein 90 (HSP90) and HSF1 would prevent the interaction between the two proteins and allow for HSF1 trimerization and target gene expression. b | Second, HSF1 could be activated using a small molecule designed to sequester the carboxy-terminal coiled-coil domain that is thought to repress HSF1 function, allowing for HSF1 trimerization. c | Last, a multivalent molecule specifically designed to bind to HSF1 monomers could bring these monomers into close proximity and increase the rate of HSF1 trimerization. AD, activation domain; DBD, DNA binding domain; LZ1, leucine zipper domain 1.

Figure 5. Importance of early intervention in neurodegenerative diseases

The progressive nature of neurodegenerative diseases complicates treatment because neuronal damage and protein misfolding are already present at the stage of symptom onset (blue line). Early intervention with heat shock transcription factor 1 (HSF1) activators that promote chaperone protein expression will ameliorate protein misfolding, slow disease progression and delay the onset of symptoms (green line). In an ideal situation, HSF1 activators could be combined with currently available symptomatic treatments at the stage of symptom onset to further enhance disease management. By contrast, HSF1-based therapeutic strategies are unlikely to be as effective at a late stage owing to the severity of neuronal loss and protein-misfolding pathology that is unlikely to be reversed (pink line). In late-stage neurodegenerative disease, alternative or combination therapies — such as inducers of autophagy coupled with chaperone protein-based therapies — may be more effective.