The central role of heat shock factor 1 in synaptic fidelity and memory consolidation.
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.
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. phoopermd@gmail.com.
Philip L
PL
Hooper
Department of Neurology/Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Heather D
HD
Durham
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary.
Zsolt
Z
Török
Department of Anthropology, Emory University, 1557 Dickey Drive, Atlanta, GA, USA.
Paul L
PL
Hooper
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary.
Tim
T
Crul
Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary.
László
L
Vígh
D000818:Animals; D003071:Cognition; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression; D000076249:Heat Shock Transcription Factors; D006801:Humans; D000069077:Memory Consolidation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D009419:Nerve Tissue Proteins; D014157:Transcription Factors
AMPAR; Aggregation; Alzheimer’s; Amyloid; B12; BDNF; CaMKII; Calcium; Calcium channel; Celastrol; Cognitive function; Consolidation; Curcumin; Dementia; Diabetes; Drug discovery; Emotion; Ethanol; Exercise; Fear; Fidelity; GGA; GSK3; Glutamate; HSF1; HSP90 inhibitor; Heat shock factor 1; Heat shock proteins; Herbs; Hippocampus; Huntingtin; Hyperthermia; Insulin; Integrin; Lipid rafts; Memory; NMDAR; Neurodegenerative disease; Neuron survival; Parkinson’s; Resveratrol; SAP97; SIRT1; Scaffolding proteins; Stress; Synapse; Synapse, heat shock; Synapsin, PSD95; Synaptic spines; Synaptophysin; TRP; Therapy; Xenohormetic; α-Synuclein