Notes

Msx1 haploinsufficiency modifies your Pax9-deficient cardiovascular phenotype.
Phosphorylation at serine residues by CK1 and CK2 modulates its intracellular localization and its sensitivity to kinases or phosphatases. Modeling studies provide evidence that the signaling pathways including DARPP-32 are endowed of strong robustness and bistable properties favoring switch-like responses. Thus DARPP-32 combined with a set of other distinct signaling molecules enriched in striatal projection neurons plays a key role in the characteristic properties and physiological function of these neurons.Decades of research led by Paul Greengard identified protein phosphorylation as a ubiquitous and vital post-translational modification involved in many neuronal signaling pathways. In particular, his discovery that second messenger-regulated protein phosphorylation plays a central role in the propagation and transduction of signals in the nervous system has been essential in understanding the molecular mechanisms of neuronal communication. The establishment of dopamine (DA) as an essential neurotransmitter in the central nervous system, combined with observations that DA activates G-protein-coupled receptors to control the production of cyclic adenosine monophosphate (cAMP) in postsynaptic neurons, has provided fundamental insight into the regulation of neurotransmission. Notably, DA signaling in the striatum is involved in many neurological functions such as control of locomotion, reward, addiction, and learning, among others. This review focuses on the history, characterization, and function of cAMP-mediated regulation of serine/threonine protein phosphatases and their role in DA-mediated signaling in striatal neurons. Several small, heat- and acid-stable proteins, including DARPP-32, RCS, and ARPP-16/19, were discovered by the Greengard laboratory to be regulated by DA- and cAMP signaling, and found to undergo a complex but coordinated sequence of phosphorylation and dephosphorylation events. These studies have contributed significantly to the establishment of protein phosphorylation as a ubiquitous and vital process in signal propagation in neurons, paradigm shifting discoveries at the time. Understanding DA-mediated signaling in the context of signal propagation has led to numerous insights into human conditions and the development of treatments and therapies.Neurodegenerative diseases (NDDs) are in need of new drug discovery approaches. Our previous systematic analyses of Huntington's Disease (HD) literature for protein-protein interactors (PPIs) and modifiers of mutant Huntingtin-driven phenotypes revealed enrichment for PPIs of genes required for homeostatic synaptic plasticity (HSP) and exosome (EV) function and exosomal proteins, which in turn highly overlapped each other and with PPIs of genes associated with other NDDs. We proposed that HSP and EVs are linked to each other and are also involved in NDD pathophysiology. Recent studies showed that HSP is indeed altered in HD and AD, and that presynaptic homeostatic plasticity in motoneurons compensates for ALS pathology. Eliminating it causes earlier degeneration and death. If this holds true in other NDDs, drug discovery in animal models should then include elucidation of homeostatic compensation that either masks phenotypes of physiologically expressed mutant genes or are overridden by their overexpression. In this new conceptual framework, enhancing such underlying homeostatic compensation forms the basis for novel therapeutic strategies to slow progression of NDDs. Moreover, if EVs are linked to HSP, then their ability to penetrate the brain, target cell types, deliver miRNA and other molecules can be leveraged to develop attractive drug modalities. Testing this new framework is posed as four questions on model development and mechanistic studies progressing from higher throughput platforms to mouse models. Similar approaches may apply to other CNS disorders including schizophrenia, autism, Rett and Fragile X syndromes due to potential links of their susceptibility genes to HSP and EVs.Schizophrenia is associated with a tremendous individual and societal burden. The disease is characterized by a complex set of symptoms including psychosis, hallucinations, delusions and related positive symptoms combined with social function deficits, cognitive disturbances and, often, devastating mood disorder, such as comorbid depression. Management of the disease often requires lifelong pharmacotherapy. However, many pharmacotherapies do not improve all symptoms (e.g., social withdrawal, depression, cognitive deficits) and can be associated with intolerable side effects such as weight gain and metabolic disturbances, motor dysfunction and endocrine dysregulation. Lumateperone (ITI-007, CAPLYTA™) is a novel antipsychotic agent, discovered and developed by Intra-Cellular Therapies, Inc. (ITCI) and approved for treatment of schizophrenia in adults in December 2019. Lumateperone simultaneously modulates serotonin, dopamine and glutamate neurotransmission, three key neurotransmitters implicated in schizophrenia. It achieves efficacy with a favorable safety profile. ARV-825 nmr The clinical development program included 20 clinical trials with over 1900 individuals exposed to lumateperone. The program demonstrated the efficacy for lumateperone in two positive well controlled trials in patients with schizophrenia. The unique pharmacology of lumateperone supports the observed benefits across a wide range of symptoms, including social function and depression, and supports its favorable safety profile. Here, we review the discovery of lumateperone's unique biological effects and its clinical actions in the treatment of schizophrenia.Presenilin 1 (PS1) is an intramembrane protease, the active subunit of the γ-secretase complex. Its well-studied function is the amyloidogenic cleavage of the C-terminal fragment of the amyloid precursor protein, also known as C99, to produce the Abeta peptide. Recent findings from the Greengard laboratory suggest that PS1 also have anti-amyloidogenic activities, which reduce Abeta levels. First, it redirects APP-C99 toward autophagic degradation, lowering the amount that can be converted into Abeta. The protein kinase CK1γ2 phosphorylates PS1 at Ser367. Phosphorylated PS1 at this position interacts with Annexin A2, which, in turn, interacts with the lysosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8. Annexin A2 facilitates the binding of Vamp8 to the autophagosomal SNARE Syntaxin 17 to modulate the fusion of autophagosomes with lysosomes. Thus, PS1 phosphorylated at Ser367 has an anti-amyloidogenic function, promoting autophagosome-lysosome fusion and increasing C99 degradation. Second, it enhances the ability of microglia to phagocyte and degrade extracellular Abeta oligomer, through regulating the expression of the lysosomal master regulator TFEB. Thus, PS1 has a role in both the production and the clearance of Abeta. Drugs designed to activate CK1γ2 and increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer's disease.N-acylphosphatidylethanolamines (NAPEs) are glycerophospholipid precursors for bioactive lipid amides and potential regulators of membrane function. They are hydrolyzed by NAPE-specific phospholipase D (NAPE-PLD) and have been implicated in neurodegenerative disorders such as Parkinson's disease. Here, we used siRNA-mediated silencing of NAPE-PLD in human SH-SY5Y cells and NAPE-PLD-/- mice to determine whether NAPEs influence the membrane association of LRRK2, a multifunctional protein kinase that is frequently mutated in persons with sporadic Parkinson's disease. NAPE-PLD deletion caused a significant accumulation of non-metabolized NAPEs, which was accompanied by a shift of LRRK2 from membrane to cytosol and a reduction in total LRRK2 content. Conversely, exposure of intact SH-SY5Y cells to bacterial PLD lowered NAPE levels and enhanced LRRK2 association with membranes. The results suggest that NAPE-PLD activity may contribute to the control of LRRK2 localization by regulating membrane NAPE levels.More than a scientific paper or a review article, this is a remembrance of a unique time of science and life that the authors spent in Paul Greengard's laboratory at the Rockefeller University in New York in the 1980s and 1990s, forming the so-called synaptic vesicle group. It was a time in which the molecular mechanisms of synaptic transmission and the nature of the organelles in charge of storing and releasing neurotransmitter were just beginning to be understood. It was an exciting time in which the protein composition of synaptic vesicles started to be identified. It turned out that the interactions of synaptic vesicle proteins with the cytoskeleton and the presynaptic membrane and their modulation by protein phosphorylation represented an essential network regulating the efficiency of neurotransmitter release and thereby synaptic strength and plasticity. This is also a description of the distinct scientific journeys that the three authors took on going back to Europe and how they were strongly influenced by the generous and outstanding mentorship of Paul Greengard, his genuine interest in their lives and careers and the life-long friendship with him.Beyond their rapid rewarding effects, drugs of abuse can durably alter an individual's response to their environment as illustrated by the compulsive drug seeking and risk of relapse triggered by drug-associated stimuli. link2 The persistence of these associations even long after cessation of drug use demonstrates the enduring mark left by drugs on brain reward circuits. However, within these circuits, neuronal populations are differently affected by drug exposure and growing evidence indicates that relatively small subsets of neurons might be involved in the encoding and expression of drug-mediated associations. The identification of sparse neuronal populations recruited in response to drug exposure has benefited greatly from the study of immediate early genes (IEGs) whose induction is critical in initiating plasticity programs in recently activated neurons. In particular, the development of technologies to manipulate IEG-expressing cells has been fundamental to implicate broadly distributed neuronal ensembles coincidently activated by either drugs or drug-associated stimuli and to then causally establish their involvement in drug responses. In this review, we summarize the literature regarding IEG regulation in different learning paradigms and addiction models to highlight their role as a marker of activity and plasticity. As the exploration of neuronal ensembles in addiction improves our understanding of drug-associated memory encoding, it also raises several questions regarding the cellular and molecular characteristics of these discrete neuronal populations as they become incorporated in drug-associated neuronal ensembles. link3 We review recent efforts towards this goal and discuss how they will offer a more comprehensive understanding of addiction pathophysiology.Signal transduction designates the set of molecular events that take place within a cell upon extracellular stimulation to mediate a functional outcome. Decades after the discovery that dopamine triggers opposing signaling pathways in D1- and D2-expressing medium spiny neurons, it is now clear that there are as many different flavors of signaling pathways in the brain as there are neuron types. One of the biggest challenges in molecular neuroscience is to elucidate cell-type specific signaling, in order to understand neurological diseases with regional vulnerability, but also to identify targets for precision drugs devoid of off-target effects. Here, we make a case for the importance of the study of neuron-type specific molecular characteristics. We then review the technologies that exist to study neurons in their full diversity and highlight their disease-relevant idiosyncrasies.
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