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Nitric oxide (NO) is an important gasotransmitter molecule that is involved in numerous physiological processes throughout the nervous system. In addition to its involvement in physiological plasticity processes (long-term potentiation, LTP; long-term depression, LTD) which can include NMDAR-mediated calcium-dependent activation of neuronal nitric oxide synthase (nNOS), new insights into physiological and pathological consequences of nitrergic signalling have recently emerged. In addition to the canonical cGMP-mediated signalling, NO is also implicated in numerous pathways involving posttranslational modifications. In this review we discuss the multiple effects of S-nitrosylation and 3-nitrotyrosination on proteins with potential modulation of function but limit the analyses to signalling involved in synaptic transmission and vesicular release. Here, crucial proteins which mediate synaptic transmission can undergo posttranslational modifications with either pre- or postsynaptic origin. During normal brain function, both pathways serve as important cellular signalling cascades that modulate a diverse array of physiological processes, including synaptic plasticity, transcriptional activity, and neuronal survival. In contrast, evidence suggests that aging and disease can induce nitrosative stress via excessive NO production. Consequently, uncontrolled S-nitrosylation/3-nitrotyrosination can occur and represent pathological features that contribute to the onset and progression of various neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s.

Prion diseases, also known as transmissible spongiform encephalopathies, are rare, progressive, and fatal neurodegenerative disorders, which are caused by the accumulation of the misfolded cellular prion protein (PrP C ). The resulting cytotoxic prion species, referred to as the scrapie prion isoform (PrP Sc ), assemble in aggregates and interfere with neuronal pathways, ultimately rendering neurons dysfunctional. As the prion protein physiologically interacts with redox-active metals, an altered redox balance within the cell can impact these interactions, which may lead to and facilitate further misfolding and aggregation. The initiation of misfolding and the aggregation processes will, in turn, induce microglial activation and neuroinflammation, which leads to an imbalance in cellular redox homeostasis and enhanced redox stress. Potential approaches for therapeutics target redox signalling, and this review illustrates the pathways involved in the above processes.

The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.

The p53 family member TAp73 is a transcription factor that plays a key role in many biological processes, including neuronal development. In particular, we have shown that p73 drives the expression of miR-34a, but not miR-34b and c, in mouse cortical neurons. miR-34a in turn modulates the expression of synaptic targets including synaptotagmin-1 and syntaxin-1A. Here we show that this axis is retained in mouse ES cells committed to differentiate toward a neurological phenotype. Moreover, overexpression of miR-34a alters hippocampal spinal morphology, and results in electrophysiological changes consistent with a reduction in spinal function. Therefore, the TAp73/miR-34a axis has functional relevance in primary neurons. These data reinforce a role for miR-34a in neuronal development.

Kv3 potassium currents mediate rapid repolarisation of action potentials (APs), supporting fast spikes and high repetition rates. Of the four Kv3 gene family members, Kv3.1 and Kv3.3 are highly expressed in the auditory brainstem and we exploited this to test for subunit-specific roles at the calyx of Held presynaptic terminal in the mouse. Deletion of Kv3.3 (but not Kv3.1) reduced presynaptic Kv3 channel immunolabelling, increased presynaptic AP duration and facilitated excitatory transmitter release; which in turn enhanced short-term depression during high-frequency transmission. The response to sound was delayed in the Kv3.3KO, with higher spontaneous and lower evoked firing, thereby reducing signal-to-noise ratio. Computational modelling showed that the enhanced EPSC and short-term depression in the Kv3.3KO reflected increased vesicle release probability and accelerated activity-dependent vesicle replenishment. We conclude that Kv3.3 mediates fast repolarisation for short precise APs, conserving transmission during sustained high-frequency activity at this glutamatergic excitatory synapse.

Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release.

Many neurodegenerative conditions and age-related neuropathologies are associated with increased levels of reactive oxygen species (ROS). The cap \"n\" collar (CncC) family of transcription factors is one of the major cellular system that fights oxidative insults, becoming activated in response to oxidative stress. This transcription factor signaling is conserved from metazoans to human and has a major developmental and disease-associated relevance. An important mammalian member of the CncC family is nuclear factor erythroid 2-related factor 2 (Nrf2) which has been studied in numerous cellular systems and represents an important target for drug discovery in different diseases. CncC is negatively regulated by Kelch-like ECH associated protein 1 (Keap1) and this interaction provides the basis for a homeostatic control of cellular antioxidant defense. We have utilized the model system to investigate the roles of CncC signaling on longevity, neuronal function and circadian rhythm. Furthermore, we assessed the effects of CncC function on larvae and adult flies following exposure to stress. Our data reveal that constitutive overexpression of CncC modifies synaptic mechanisms that positively impact on neuronal function, and suppression of CncC inhibitor, Keap1, shows beneficial phenotypes on synaptic function and longevity. Moreover, supplementation of antioxidants mimics the effects of augmenting CncC signaling. Under stress conditions, lack of CncC signaling worsens survival rates and neuronal function whilst silencing Keap1 protects against stress-induced neuronal decline. Interestingly, overexpression and RNAi-mediated downregulation of CncC have differential effects on sleep patterns possibly interactions with redox-sensitive circadian cycles. Thus, our data illustrate the important regulatory potential of CncC signaling in neuronal function and synaptic release affecting multiple aspects within the nervous system.

Total and N-terminal isoform selective p73 knockout mice show a variety of central nervous system defects. Here we show that TAp73 is a transcriptional activator of p75 neurotrophin receptor (p75 ᴺᵀᴿ) and that p75 ᴺᵀᴿ mRNA and protein levels are strongly reduced in the central and peripheral nervous systems of p73 knockout mice. In parallel, primary cortical neurons from p73 knockout mice showed a reduction in neurite outgrowth and in nerve growth factor-mediated neuronal differentiation, together with reduced miniature excitatory postsynaptic current frequencies and behavioral defects. p73 null mice also have impairments in the peripheral nervous system with reduced thermal sensitivity, axon number, and myelin thickness. At least some of these morphological and functional impairments in p73 null cells can be rescued by p75 ᴺᵀᴿ re-expression. Together, these data demonstrate that loss of p75 ᴺᵀᴿ contributes to the neurological phenotype of p73 knockout mice.

Neurodegenerative disorders are often associated with cellular dysfunction caused by underlying protein-misfolding signalling. Numerous neuropathologies are diagnosed at late stage symptomatic changes which occur in response to these molecular malfunctions and treatment is often too late or restricted only to the slowing of further cell death. Important new strategies to identify early biomarkers with predictive value to intervene with disease progression at stages where cell dysfunction has not progressed irreversibly is of paramount importance. Thus, the identification of these markers presents an essential opportunity to identify and target disease pathways. This review highlights some important metabolic alterations detected in neurodegeneration caused by misfolded prion protein and discusses common toxicity pathways identified across different neurodegenerative diseases. Thus, having established some commonalities between various degenerative conditions, detectable metabolic changes may be of extreme value as an early diagnostic biomarker in disease.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterised by progressive degeneration of the motor neurones. An expanded GGGGCC (G4C2) hexanucleotide repeat in C9orf72 is the most common genetic cause of ALS and frontotemporal dementia (FTD); therefore, the resulting disease is known as C9ALS/FTD. Here, we employ a Drosophila melanogaster model of C9ALS/FTD (C9 model) to investigate a role for specific medium-chain fatty acids (MCFAs) in reversing pathogenic outcomes. Drosophila larvae overexpressing the ALS-associated dipeptide repeats (DPRs) in the nervous system exhibit reduced motor function and neuromuscular junction (NMJ) defects. We show that two MCFAs, nonanoic acid (NA) and 4-methyloctanoic acid (4-MOA), can ameliorate impaired motor function in C9 larvae and improve NMJ degeneration, although their mechanisms of action are not identical. NA modified postsynaptic glutamate receptor density, whereas 4-MOA restored defects in the presynaptic vesicular release. We also demonstrate the effects of NA and 4-MOA on metabolism in C9 larvae and implicate various metabolic pathways as dysregulated in our ALS model. Our findings pave the way to identifying novel therapeutic targets and potential treatments for ALS.