PSD95

A surge of a neural-specific protein in the brain is the earliest-yet biomarker for Alzheimer's disease, report researchers studying a mouse model of the disease. Furthermore, the increased protein activity leads to the seizures associated with the earliest stages of neurodegeneration, and inhibiting the protein in the mice slowed the onset and progression of seizure activity. The neural-specific protein, PSD-95, could pose a new target for Alzheimer's research, early diagnosis and treatment. A surge of a neural-specific protein in the brain is the earliest-yet biomarker for Alzheimer's disease, report University of Illinois Urbana-Champaign researchers studying a mouse model of the disease. Furthermore, the increased protein activity leads to the seizures associated with the earliest stages of neurodegeneration, and inhibiting the protein in the mice slowed the onset and progression of seizure activity. The neural-specific protein, PSD-95, could pose a new target for Alzheimer's research, early diagnosis and treatment, said study leader Nien-Pei Tsai, an Illinois professor of molecular and integrative physiology. Tsai's group studies mice that make more of the proteins that form amyloid-beta, which progressively aggregates in Alzheimer's disease to form plaques in the brain that hamper neural activity. However, in the new work, the group focused on a time frame much earlier in the mouse lifespan than others have studied -- when no other markers or abnormalities have been reported, Tsai said. "We were thinking, if we can catch anything that is happening early enough, maybe we can find a way to diagnose the disease earlier or slow down the progression," Tsai said. "We know that Alzheimer's is irreversible. But if we can slow down the progression or even delay the onset of the disease, we can improve the quality of life for patients." While watching early neural development, first in neuron cultures and then in live mice, the researchers saw an elevation in PSD-95 levels. The PSD-95 protein's job is to attract and pull other receptors to the synaptic surface -- the space where two neurons pass signals to one another. "Our data suggests that the elevated PSD-95 is contributing to hyperexcitability in the brain. That's a common phenotype is some of the early stages of Alzheimer's disease patients: They tend to have hyperexcitability or elevated seizure susceptibility in the brain, preceding and exacerbating the neurodegeneration that follows," said Tsai, who also is affiliated with the Beckman Institute of Advanced Science and Technology at the U. of I. To confirm that increased PSD-95 was a driving force behind the seizure activity, the researchers inhibited PSD-95 in a mouse cohort. They saw reduced receptor activity at the synapse, fewer seizures in the mice and reduced mortality from seizures. "Our findings show that PSD-95 is a critical contributor to the hyperexcitability in the earliest stages of Alzheimer's. So we think that PSD-95 can be an early biomarker to indicate that a patient could have Alzheimer's disease or elevated seizure susceptibility. In terms of treatment, antibody inhibitors for PSD-95 could be useful in the early onset of Alzheimer's, with more clinical study." The group published its findings in the journal EMBO Reports. The researchers hope to partner with clinical research teams to determine whether their findings in mice correlate with samples from human patients. They also plan to study other receptors that PSD-95 interacts with on the synaptic surface to see if it plays a role in other symptoms of the disease or stages of its progression. "For example, the NMDA receptor has been shown to contribute to neural cell death in Alzheimer's disease. So we're trying to see whether by inhibiting PSD-95, we also can inhibit this particular NMDA receptor to slow down cell death." The National Institutes of Health and the Alzheimer's Association supported this work. The National Institute of Health supported this work through grants R01NS105615, R01MH124827 and R21AG071278.

Neuroscientists say they have found a new function for the SYNGAP1 gene, a DNA sequence that controls memory and learning in mammals, including mice and humans. Johns Hopkins Medicine neuroscientists say they have found a new function for the SYNGAP1 gene, a DNA sequence that controls memory and learning in mammals, including mice and humans. The finding, published March 1 in Science, may affect the development of therapies designed for children with SYNGAP1 mutations, who have a range of neurodevelopmental disorders marked by intellectual disability, autistic-like behaviors, and epilepsy. In general, SYNGAP1, as well as other genes, control learning and memory by making proteins that regulate the strength of synapses -- the connections between brain cells. Previously, the researchers say, the SYNGAP1 gene was thought to work exclusively by encoding a protein that behaves like an enzyme, regulating chemical reactions that lead to changes in the strength of synapses. Now, the scientists say, their experiments in mice show that protein encoded by the gene may also function more like a so-called scaffolding protein that regulates synaptic plasticity, or how synapses get stronger or weaker over time, independent of its enzyme activity. The SynGAP protein appears to act as a traffic manager, they say, directing where and what brain proteins are at synapses. With his team, Richard Huganir, Ph.D., Bloomberg Distinguished Professor of Neuroscience and Psychological and Brain Sciences and director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine, first isolated the SYNGAP1 gene in 1998. SynGAP proteins are very abundant at the synapse, says Huganir, and it has long been thought that SynGAP's main role was to spark enzymatic chemical reactions that regulate synapse strength. But, working with the SynGAP protein, Huganir and others had begun to see that SynGAP proteins have a strange property when they interact with the major synaptic scaffolding protein, PSD-95. They morph into liquid droplets. "For an enzymatic protein, that structural transformation is unusual," says Huganir. To tease out and understand the purpose of SynGAP's peculiar liquid transformation, Huganir, neuroscience instructor Yoichi Araki and Huganir's research team at Johns Hopkins designed experiments in neurons in which they inserted mutations in the so-called GAP domain of the SYNGAP1 gene that would remove the enzymatic function of SynGAP without affecting its structure. The Johns Hopkins team found that, even without the enzymatic activity, the synapse worked normally, suggesting that the structural property alone is very important for SynGAP function. The research team next did the same type of genetic engineering in mice to remove the enzymatic function of SynGAP, and found similar results: Synapses behaved normally, with no problems in synaptic plasticity, and the mice had no difficulty in learning and memory behaviors. The research team says this indicates that SynGAP's structural property was sufficient for normal cognitive behavior. To understand how SynGAP's structure regulates synapses, the scientists analyzed synapses more closely to find that SynGAP protein competed with the binding of AMPA receptor/TARP complexes, a bundle of neurotransmitter proteins that strengthens synapses, and the PSD-95 scaffolding protein. The experiments suggest that, at rest, SynGAP tightly binds to PSD-95, not allowing it to bind to any other proteins in the synapse. However, during synaptic plasticity, learning and memory, SynGAP protein disconnected from PSD-95, left the synapse and allowed neurotransmitter receptor complexes to bind to PSD-95. This made the synapse stronger and increased transmission between brain cells. "This sequence happens without the catalytic activity typical of SynGAP," says Huganir. Rather, SynGAP corrals PSD-95 when bound to it, but when SynGAP leaves this synapse, PSD-95 is open to bind to AMPA receptor/TARP complexes. In children with SynGAP mutations, about half the number of SynGAP proteins are in the synapse. With fewer SynGAP proteins, PSD-95 may bind more with the AMPA receptor/TARP complexes, changing neuronal connections and creating the increased brain cell activity characteristic of epileptic seizures common among children with SynGAP mutations. Huganir says that both functions of SynGAP -- enzymatic and the "traffic management" action of a scaffolding protein -- may now be important in finding treatments for SynGAP-related neurodevelopmental disorders. Their research also suggests that targeting just one function of SynGAP alone may not be enough to have a significant impact. In addition to Araki and Huganir, Johns Hopkins scientists who authored the report on the research are Kacey Rajkovich, Elizabeth Gerber, Timothy Gamache, Richard Johnson, Thanh Hai Tran, Bian Liu, Qianwen Zhu, Ingie Hong and Alfredo Kirkwood. Funding for the research was provided by the National Institutes of Health (R01MH112151, R01NS036715, T32MH015330) and the SynGAP Research Fund.

Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences. In a new study in Biological Psychiatry, published by Elsevier, researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model. Jing Zhang, PhD, at Fujian Medical University and senior author of the study, said, "Emerging evidence suggests that MDD is a consequence of the co-work of genetic risks and environmental factors, so it is crucial to explore how stress exposure and risk genes co-contribute to the pathogenesis of MDD." To do that, the authors used a mouse model of stress-induced depression called chronic social defeat stress (CSDS) in which mice are exposed to aggressor mice daily for two weeks. They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Increased expression of LHPP in the stressed mice aggravated the depression-like behaviors by decreasing expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure. Dr. Zhang noted, "Interestingly, LHPP mutations (E56K, S57L) in humans can enhance CaMKIIα/ERK-BDNF/PSD95 signaling, which suggests that carrying LHPP mutations may have an antidepressant effect in the population." MDD is an extremely heterogeneous condition. Differences in the types of depression experienced by people influence the way they respond to treatment. A large subgroup of people with depression fail to respond to standard antidepressant medications and have "treatment-resistant" symptoms of depression. These patients often respond to different medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine markedly alleviated LHPP-induced depression-like behaviors, whereas the traditional drug fluoxetine did not, suggesting that the mechanism might underlie some types of treatment-resistant depression. John Krystal, MD, Editor of Biological Psychiatry, said of the work, "We have limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a depression risk mechanism for stress-related behaviors that fail to respond to a standard antidepressant but respond well to ketamine. This may suggest that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression." Dr. Zhang added, "Together, our findings identify LHPP as an essential player driving stress-induced depression, implying targeting LHPP as an effective strategy in MDD therapeutics in the future."