Abstract
Networks of neuronal synapses are the fundamental basis for making and retaining memory. Reduced synapse number and quality correlates with loss of memory in dementia. Heat shock factor 1 (HSF1), the major transcription factor regulating expression of heat shock genes, plays a central role in proteostasis, in establishing and sustaining synaptic fidelity and function, and in memory consolidation. Support for this thesis is based on these observations: (1) heat shock induces improvements in synapse integrity and memory consolidation; (2) synaptic depolarization activates HSF1; (3) activation of HSF1 alone (independent of the canonical heat shock response) augments formation of essential synaptic elements—neuroligands, vesicle transport, synaptic scaffolding proteins, lipid rafts, synaptic spines, and axodendritic synapses; (4) HSF1 coalesces and activates memory receptors in the post-synaptic dendritic spine; (5) huntingtin or α-synuclein accumulation lowers HSF1 while HSF1 lowers huntingtin and α-synuclein aggregation—a potential vicious cycle; and (6) HSF1 agonists (including physical activity) can improve cognitive function in dementia models. Thus, via direct gene expression of synaptic elements, production of HSPs that assure high protein fidelity, and activation of other neuroprotective signaling pathways, HSF1 agonists could provide breakthrough therapy for dementia-associated disease.
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Acknowledgments
Tim Crul was funded by OTKA PD109539 and Laszlo Vigh and Zsolt Torok by OTKA NK100857 and OTKA NN111006.
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Hooper, P.L., Durham, H.D., Török, Z. et al. The central role of heat shock factor 1 in synaptic fidelity and memory consolidation. Cell Stress and Chaperones 21, 745–753 (2016). https://doi.org/10.1007/s12192-016-0709-1
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DOI: https://doi.org/10.1007/s12192-016-0709-1
Keywords
- HSF1
- Heat shock factor 1
- Memory
- Synapse, heat shock
- Heat shock proteins
- Synapse
- Synapsin, PSD95
- Synaptophysin
- SAP97
- Celastrol
- B12
- Exercise
- Hyperthermia
- Fear
- Emotion
- Stress
- Dementia
- Alzheimer’s
- Neurodegenerative disease
- TRP
- Ethanol
- Resveratrol
- SIRT1
- GSK3
- Curcumin
- Xenohormetic
- Insulin
- Diabetes
- Calcium
- Glutamate
- NMDAR
- AMPAR
- HSP90 inhibitor
- Consolidation
- Fidelity
- Neuron survival
- Drug discovery
- Therapy
- Cognitive function
- Scaffolding proteins
- Lipid rafts
- Synaptic spines
- Integrin
- Hippocampus
- Amyloid
- BDNF
- Huntingtin
- α-Synuclein
- Parkinson’s
- Aggregation
- Herbs
- GGA
- CaMKII
- Calcium channel