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HPF1 as a regulator of exercise-driven neuroplasticity and memory consolidation
Location: 10
Mentor: Dr. Claes Wahlestedt
Background: Memory formation involves molecular processes such as protein phosphorylation, histone modification, and neurotrophic gene expression. While PARP1 activity is essential for memory, the specific functions required for neurotrophic gene expression remain unclear. Histone PARylation factor 1 (HPF1) forms a complex with PARP1, directing its activity toward histone proteins. This study investigates HPF1’s role in neuronal memory signaling using in vitro and in vivo models. Methods: N2A cells were transfected with siRNA to silence HPF1, followed by hydrogen peroxide (H₂O₂) or Forskolin (FSK) treatment to activate memory-related pathways. Protein analysis (Western blot, ELISA) and RT-qPCR assessed key markers such as ERK2 phosphorylation, histone mono-ADP-ribosylation (H3 MAR), and BDNF expression. In vivo experiments examined aging and disease-related effects on ADP-ribosylation and memory signaling. Young adult mice underwent a single 40-minute session of acute aerobic exercise using a treadmill with progressive speed increase. Mice were euthanized at 0, 2, 6, or 24 hours post-exercise, and hippocampal tissue was collected. RT-qPCR evaluated Bdnf and Parp1 gene expression; Western blot and ELISA assessed neurotrophic signaling markers including ERK phosphorylation and ADP-ribosylation. Results: HPF1 silencing blocked ERK2 phosphorylation and H3 MAR after H₂O₂ stimulation and inhibited FSK-induced BDNF upregulation. HPF1 did not affect FSK-induced CREB phosphorylation, suggesting a downstream role. As shown by in vivo data, aging and neurodegeneration correlated with elevated histone ADP-ribosylation and altered signaling, indicating impaired neuroplasticity. Conclusion: HPF1 is essential for PARP1-driven histone modification, ERK signaling, and BDNF expression, linking it to exercise-induced memory and neurodegeneration.
