HDAC4

Researchers found that, in neurons that produced the neuropeptide NMS, the interaction between molecules SIK3 and HDAC4 has a critical role in sleep regulation through both the length of the circadian period and sleep homoeostasis. Given the similarities among different mammals, new information about how the circadian system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. Most living creatures exhibit a circadian rhythm, an internal clock that repeats around every 24 hours. Now, researchers from Japan have found new details about the molecular processes that govern sleep/wake rhythms in mice. In a recently published study, researchers from the University of Tsukuba have revealed that a key molecule involved in sleep homeostasis (called SIK3 or salt-inducible kinase 3) also plays a critical role in circadian behavior. Animals are able to adapt to the 24-hour cycle of light and dark in terms of both behavior and physiology via changes in the suprachiasmatic nucleus (SCN), which is the brain's master clock that synchronizes the various rhythms in the body. However, the biological activities within the SCN that induce time-specific wakefulness have not been fully characterized; the research team aimed to address this. "Most animals show a peak in activity at a specific point in the circadian cycle," explains lead author of the study Professor Masashi Yanagisawa. "Because the SCN has been found to regulate sleep and wakefulness at certain times of the day, we wanted to investigate the distinct neurons that control this process." To do this, the research team genetically manipulated levels of SIK3 in specific neuron groups in the SCN of mice. Then, they examined sleep and circadian behaviors in the mice, such as when and for how long the mice exhibited activity with respect to the light-dark cycle. "We found that SIK3 in the SCN can influence circadian cycle length and the timing of peak arousal activity, without changing the daily sleep amount," says Professor Yanagisawa. The research team previously reported that SIK3 interacts with LKB1 (an upstream molecule of SIK3) and HDAC4 (an important target of SIK3) in glutamatergic neurons to regulate the amount and depth of sleep. Now, they have found that the SIK3-HDAC4 pathway modulates the length of the circadian period through NMS-producing neurons, and contributes to the sleep/wake rhythm. The length of the behavioral period and the timing of peak activity are important components of the circadian rhythm. Given the similarities between the circadian systems of different mammals, new information about how this system works in mice could lead to new treatments for sleep and circadian rhythm disorders in humans. This work was supported by the World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI), Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST), Japan Agency for Medical Research and Development (AMED), JSPS DC2 grant, University of Tsukuba Basic Research Support Program Type A, and Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).

sCFH is an engineered and improved version of complement factor H. Credit: Deposition authors: Jaakola, V-P, Jokiranta, TS, Goldman, A. Visualisation author: User: Astrojan/ commons.wikimedia.org Fortress Biotech subsidiary Aevitas Therapeutics has signed an asset purchase deal to sell the proprietary rights to its short-form human complement factor H (sCFH) asset to 4D Molecular Therapeutics for $140m in cash. sCFH is an engineered and improved version of complement factor H (CFH) that can fit into adeno-associated virus (AAV) vectors with solid expression and applications confirmed in cultured human cells in vitro, in addition to various preclinical animal models in vivo. Recommended Reports Reports Bromodomain Containing Protein 4 (Protein HUNK1 or BRD4) Drugs in Development by Therapy Areas an... GlobalData Reports Histone Deacetylase 4 (Histone Deacetylase A or HDAC4 or EC 3.5.1.98) Development by Therapy Area... GlobalData View all Reinstating CFH function by employing the sCFH protein could restore normal complement regulation and minimise retinal injury that manifests as progressive geographic atrophy (GA). Aevitas will receive the payment as potential late-stage development, regulatory and sales milestones. The firm will also receive single-digit royalties on net sales. 4DMT will be responsible for licence payments to the University of Pennsylvania, where the Perelman School of Medicine’s pharmacology professor, Dr Wenchao Song, jointly invented and developed the sCFH technology. Fortress chairman, president and CEO and Aevitas executive chairman Lindsay A Rosenwald stated: “This agreement with 4DMT allows Fortress to focus on acquiring and developing clinical-stage treatments, while potentially expediting the development and commercialisation of this preclinical sCFH technology. “Partnering with 4DMT further validates the Fortress business model of identifying and developing promising treatments for patients, while pursuing opportunities that potentially maximise shareholder value. “We look forward to 4DMT using their vector platform to continue the development of the sCFH asset to potentially treat geographic atrophy (GA) and other diseases.”

Researchers have identified a signaling pathway that regulates sleep. By studying genetic mutations in mice, they were able to show that an enzyme called histone deacetylase 4 (HDAC4), which is known to suppress gene expression, plays a key role in regulating the amount and depth of sleep. Further experiments revealed that this regulatory signaling in the excitatory neurons of the cortex and hypothalamus regulates sleep quantity and quality, respectively. A good night's sleep can work wonders for both mind and body. But what is it that determines how much we need to sleep, and what can cause us to sleep more deeply? In a new study, researchers from the University of Tsukuba have now provided some answers, revealing a signaling pathway within brain cells that regulates the length and depth of sleep. "We examined genetic mutations in mice and how these affect their patterns of sleep," says senior author of the study, Professor Hiromasa Funato. "We identified a mutation that led to the mice sleeping much longer and more deeply than usual." The researchers found that this was caused by low levels of an enzyme called histone deacetylase 4 (HDAC4), which is known to suppress the expression of target genes. Previous studies on HDAC4 have shown that it is greatly affected by the attachment of phosphate molecules in a process known as phosphorylation. When this occurs, HDAC4 tends to move away from the cell nucleus, and the suppression of certain proteins is reduced. The researchers were interested in whether this phosphorylation of HDAC4 would affect sleep. "We focused on a protein called salt-inducible kinase 3, otherwise known as SIK3, which phosphorylates HDAC4," says Professor Funato. "We previously found that this protein has strong effects on sleep." The team found that when there was a lack of SIK3 or when HDAC4 was modified to prevent phosphorylation, the mice slept less. In contrast, when the mice had a more active version of SIK3, which increased the phosphorylation of HDAC4, they slept a lot more. They also identified a further protein, LKB1, which phosphorylates SIK3, and has similar sleep-suppressing effects when deficient. "Our findings indicate that there is a signaling pathway within brain cells from LKB1 to SIK3 and then to HDAC4," says study co-senior author, Professor Masashi Yanagisawa. "This pathway leads to the phosphorylation of HDAC4, which promotes sleep, most probably because it affects the expression of sleep-promoting genes." The team carried out further experiments to identify the brain cells in which these pathways regulate sleep. This involved altering the amounts of SIK3 and HDAC4 in different cell types and brain regions. The results indicated that signaling within the cells of the cortex regulates the depth of sleep, while signaling within the hypothalamus regulates the amount of deep sleep. For both brain regions, the excitatory neurons, which can activate other neurons, were identified as playing a key role. These results provide an important insight into how sleep is regulated, which could potentially lead to a greater understanding of sleep disorders as well as the development of new treatments. This work was supported by the World Premier International Research Center Initiative from MEXT, JSPS KAKENHI, JST CREST, AMED, JSPS DC2, University of Tsukuba Basic Research Support Program Type A, Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).