Biology subjects

Perez-Sisques, L.

Publications and source records attributed to Perez-Sisques, L..

5 recordsLinked to original sources

bioRxiv2025

Inhibition of histone lysine demethylase restores learning and memory in aged mice

Chromatin undergoes dramatic changes during the ageing process. In the brain, these chromatin changes are thought to underlie age-associated deficits in the activity-dependent gene transcription necessary for memory consolidation. Here, we show that the levels of a specific histone post-translational modification (PTM), trimethylation of lysine 4 on histone 3 (H3K4me3) is markedly increased in the hippocampus of aged mice and that the activity-induced increase in H3K4me3 that is observed in response to a learning stimulus in young mice, is severely blunted in the aged hippocampus. H3K4me3 typically marks open, accessible chromatin at the transcriptional start sites (TSSs) of actively transcribed genes. We identify altered H3K4me3 peaks at TSSs and show that ca. 90% of the activity-induced H3K4me3 changes at TSSs are either absent or reduced in the aged hippocampus. To understand the biological significance of these age-associated changes, we screened a library of pharmacological compounds for compounds that can alter H3K4me3 levels in hippocampal neurons. We show that treatment of aged mice with one of these, the LSD1 inhibitor ORY-1001, restored normal learning and memory in object location and recognition tasks. Furthermore, we show that ORY-1001 treatment increased long-term potentiation (LTP), a form of synaptic plasticity deficient in the aged hippocampus. These findings suggest that targeting the epigenetic machinery that regulates activity-dependent gene transcription may represent an avenue for treating age-associated cognitive impairment. HighlightsO_LIH3K4me3 levels are elevated in the naive aged mouse hippocampus C_LIO_LIActivity-dependent H3K4me3 induction is impaired in the aged mouse hippocampus C_LIO_LILSD1 inhibition restores learning and memory in aged mice C_LIO_LILSD1 inhibition restores activity-dependent Arc induction and increases LTP in the aged hippocampus C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/695858v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@fccd92org.highwire.dtl.DTLVardef@11c4d93org.highwire.dtl.DTLVardef@128f8b8org.highwire.dtl.DTLVardef@e1341f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Leveraging unbiased LC-MS analysis to identify histone post-translational modifications associated with age-related decline of learning and memory

Age-associated cognitive decline is a significant societal challenge, with several neurodegenerative diseases like Alzheimers disease becoming prevalent. Normal ageing is associated with several molecular, cellular, and metabolic hallmarks, including epigenetic mechanisms. In particular, dysregulation of post-translational modifications on histone tails is emerging as a mechanism associated with functional decline. The hippocampus is a region of the brain that is essential for the formation of episodic and spatial memories, which are particularly susceptible to age-related decline. In this perspective manuscript, we have used mass spectrometry as an unbiased method to profile histone tail post-translational modifications both at baseline and after contextual fear conditioning (CFC) from young and aged mouse hippocampi to identify age- and activity-dependent changes. Using this approach, we identify epigenetic marks not widely studied in ageing and in activity-induced learning. We propose a framework on how to integrate these epigenetic marks into current knowledge and discuss how to use this new analysis to formulate novel hypotheses that will broaden this field of ageing research. We believe that this work will be of interest to scientists, clinicians and the wider public by making a significant contribution to our understanding of the molecular mechanisms responsible for age-associated cognitive decline and by reporting the identification of new mechanisms to focus on.

neuroscience↗

bioRxiv2024

Deficiency of the histone lysine demethylase KDM5B causes autism-like phenotypes via increased NMDAR signalling

Loss-of-function mutations in genes encoding lysine methyltransferases (KMTs) and demethylases (KDMs) responsible for regulating the trimethylation of histone 3 on lysine 4 (H3K4me3) are associated with neurodevelopmental conditions, including autism spectrum disorder and intellectual disability. To study the specific role of H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity. These mice exhibited autism-like behaviours and increased brain size. H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex. These included elevated expression of Grin2d. The Grin2d gene product NMDAR2D was increased in synaptosomes isolated from the Kdm5b-deficient neocortex and treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalisations and reduced repetitive digging behaviours. These findings suggest that increased H3K4me3 levels and associated Grin2d gene upregulation disrupt brain development and function, leading to socio-communication deficits and repetitive behaviours, and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency. TeaserInhibitors targeting NMDA receptors may represent viable therapies for KDM5B neurodevelopmental disorders

neuroscience↗

bioRxiv2020

RTP801 Is A Key Modulator For Motor Learning

RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinsons and Huntingtons diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinsons and Huntingtons disease mouse models, RTP801 knockdown alleviates motor-learning deficits. Here, we investigated the physiological role of RTP801 in neuronal plasticity. RTP801 is found in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity in motor learning.

neuroscience↗

bioRxiv2020

SYNAPTIC RTP801 CONTRIBUTES TO MOTOR LEARNING DYSFUNCTION IN HUNTINGTON DISEASE

RTP801/REDD1 is a stress responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntingtons disease (HD) patients putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. Ectopic mhtt was over expressed in cultured rat primary neurons. The protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.

neuroscience↗