The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

• Published in: Cell stress & chaperones Vol. 21; no. 5; pp. 745 - 753
• Main Authors: Hooper, Philip L., Durham, Heather D., Török, Zsolt, Hooper, Paul L., Crul, Tim, Vígh, László
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer 01.09.2016; Springer Netherlands; Springer Nature B.V
• Subjects: Alzheimers disease; and Reflection; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Cognition; Dementia; DNA-Binding Proteins - physiology; Gene Expression; Heat Shock Transcription Factors; Humans; Immunology; Lipids; Memory; Memory Consolidation; Memory disorders; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Neurosciences; PERSPECTIVE AND REFLECTION ARTICLE; Rafts; Receptors; Shock heating; Synapses; Synapses - physiology; Transcription Factors - physiology; Transcriptional Activation; Fidelity; Therapy; α-Synuclein; Huntingtin; Heat shock factor 1; Memory; Alzheimer’s; Exercise; TRP; Integrin; GSK3; Xenohormetic; Neuron survival; Herbs; Synaptophysin; Ethanol; Glutamate; SIRT1; Insulin; HSP90 inhibitor; Calcium channel; Parkinson’s; Synapse, heat shock; Synapse; Synaptic spines; NMDAR; Drug discovery; Cognitive function; Hyperthermia; Hippocampus; Dementia; B; Calcium; Celastrol; Lipid rafts; SAP97; Aggregation; Consolidation; HSF1; Resveratrol; Neurodegenerative disease; Curcumin; Amyloid; Emotion; GGA; BDNF; Synapsin, PSD95; Heat shock proteins; AMPAR; Stress; Scaffolding proteins; Fear; CaMKII; Diabetes; B12
• ISSN: 1355-8145; 1466-1268
• DOI: 10.1007/s12192-016-0709-1

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 postsynaptic 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 break-through therapy for dementia-associated disease.