Activity

18 [1.4-7.5],p=0.008). HRQoL outcomes strongly correlated with functional outcome 42% of children demonstrated clinically significant reductions in overall PedsQL score, and poor bowel outcome was strongly associated with impaired QOL (B=22•7 [12•7-32•7],p<0•001). In adults, GIQLI scores were more often impacted in patients with extended segment disease. SF-36 scores were reduced relative to population level data in most domains, with large effect sizes noted for females in General Health (g=1.19) and Social Wellbeing (g=0.8).

Functional impairment is common after pull-through, but bowel function improves with age. Clustering of poor functional outcomes across multiple domains identifies a need for early recognition and long-term support for these patients.

Functional impairment is common after pull-through, but bowel function improves with age. Clustering of poor functional outcomes across multiple domains identifies a need for early recognition and long-term support for these patients.Paul Greengard brought to neuroscience the idea of, and evidence for, the role of second messenger systems in neuronal signaling. The fundamental nature of his contributions is evident in the far reach of his work, relevant to various subfields and topics in neuroscience. In this review, we discuss some of Greengard’s work from the perspective of nicotinic acetylcholine receptors and their relevance to nicotine addiction. Specifically, we review the roles of dopamine- and cAMP-regulated phospho-protein of 32kDa (DARPP-32) and Ca2+/calmodulin-dependent kinase II (CaMKII) in nicotine-dependent behaviors. For each protein, we discuss the historical context of their discovery and initial characterization, focusing on the extensive biochemical and immunohistochemical work conducted by Greengard and colleagues. We then briefly summarize contemporary understanding of each protein in key intracellular signaling cascades and evidence for the role of each protein with respect to systems and behaviors relevant to nicotine addiction.DARPP-32 (dopamine- and cAMP-regulated phosphoprotein with an apparent Mr of 32,000), now also known as phosphoprotein phosphatase 1 regulatory subunit 1B (PPP1R1B), is a potent inhibitor of protein phosphatase 1 (PP1, also known as PPP1) when phosphorylated at Thr34 by cAMP-dependent protein kinase (PKA). DARPP-32 exhibits a remarkable regional distribution in brain, roughly similar to that of dopamine innervation. Its discovery was a culmination of the long-standing effort of Paul Greengard to understand the mechanisms through which neurotransmitters such as dopamine exert their effects on target neurons. DARPP-32 is particularly enriched in striatal projection neurons where it is regulated by numerous signals through which it integrates and amplifies responses to many stimuli. Molecular studies of DARPP-32 have revealed that its regulation and function are more complex than anticipated. It is phosphorylated on multiple sites by several protein kinases that modulate DARPP-32 properties. Primarily, when phosphorylated at Thr34 DARPP-32 is a potent inhibitor of PP1, whereas when phosphorylated at Thr75 by Cdk5 it inhibits PKA. 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. Capsazepine cell line In this new conceptual framework, enhancing such underlying homeostatic compensation forms the basis for novel therapeutic strategies to slow progression of NDDs.