Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. ...In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.
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► JM6 is a novel prodrug that inhibits kynurenine 3-monooxygenase (KMO) ► Oral delivery of JM6 ameliorates neurodegenerative symptoms in mice ► Inhibition of KMO in the blood sends a neuroprotective signal to the brain
The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic ...acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been implicated in the pathophysiology of neurodegenerative disorders, including Huntington's disease (HD)
1. A ...central hallmark of HD is neurodegeneration caused by a polyglutamine expansion in the huntingtin (htt) protein
2. Here we exploit a transgenic
Drosophila melanogaster model of HD to interrogate the therapeutic potential of KP manipulation. We observe that genetic and pharmacological inhibition of kynurenine 3-monooxygenase (KMO) increases levels of the neuroprotective metabolite kynurenic acid (KYNA) relative to the neurotoxic metabolite 3-hydroxykynurenine (3-HK) and ameliorates neurodegeneration. We also find that genetic inhibition of tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting step in the pathway, leads to a similar neuroprotective shift toward KYNA synthesis. Importantly, we demonstrate that the feeding of KYNA and 3-HK to HD model flies directly modulates neurodegeneration, underscoring the causative nature of these metabolites. This study provides the first genetic evidence that inhibition of KMO and TDO activity protects against neurodegenerative disease in an animal model, indicating that strategies targeted at two key points within the KP may have therapeutic relevance in HD, and possibly other neurodegenerative disorders.
► Mutant htt flies are sensitized to increased flux through the central KP ► Genetic inhibition of KMO or TDO is neuroprotective ► KMO inhibitors ameliorate neurodegeneration ► Neurodegeneration is directly modulated by 3-HK and KYNA
Diapycnal mixing impacts vertical transport rates of salt, heat, and other dissolved substances, essential for the overturning circulation and ecosystem functioning in marine systems. While most ...studies have focused on mixing induced by individual obstacles in tidal flows, we investigate the net effect of non‐tidal flow over multiple small‐scale (<1 km) bathymetric features penetrating a strongly‐stratified density interface in a coastal region. We combine high‐resolution broadband acoustic observations of turbulence microstructure with traditional shear microstructure profiling, to resolve the variability and intermittency of stratified turbulence related to the rough bathymetry. Scale analysis and acoustic imaging suggest that underlying mixing mechanisms are related to topographic wake eddies and breaking internal waves. Depth averaged dissipation rates (1.1 × 10−7 Wkg−1) and turbulent vertical diffusivities (7 × 10−4 m2s−1) in the halocline exceed reference values by two orders of magnitude. Our study emphasizes the importance of rough small‐scale bathymetric features for the vertical transport of salt in coastal areas.
Plain Language Summary
Mixing of water across density interfaces is important for ecosystems and the circulation between basins. However, mixing related to rough small‐scale bathymetry is often not resolved in models and difficult to measure. In this study, we show high‐resolution acoustic observations of intense vertical mixing across a strong density interface, that separates the saltier bottom water from the fresher surface water in the northern Baltic Sea. In the study region, steep underwater hills and ridges extend into the density interface. As water flows over the region, the hills and ridges cause the water to mix. Measured values of mixing and vertical salt fluxes in this region are up to two orders of magnitude higher than at a nearby reference station with smooth bathymetry. Our analysis suggests that the observed high mixing is mainly caused by eddies in the wake of obstacles and secondarily by breaking internal waves, which are waves within the water that occur on interfaces between layers with different properties. Understanding mixing mechanisms and estimating their contribution to the total mixing is needed to implement mixing into ocean models. This study highlights the importance of rough small‐scale (<1 km) seafloor features for mixing and vertical transport of salt.
Key Points
High‐resolution turbulence observations in a coastal, strongly stratified region with extremely rough seafloor topography
Acoustic turbulence imaging shows highly intermittent and localized mixing due to wake eddies and internal‐wave breaking near obstacles
Turbulent diffusivities and transport rates of salt increased by two orders of magnitude inside mixing hotspots near rough bathymetry
Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular ...chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Huntington's disease (HD) is an adult onset neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein. Recent work has shown that perturbation of kynurenine pathway (KP) ...metabolism is a hallmark of HD pathology, and that changes in brain levels of KP metabolites may play a causative role in this disease. The KP contains three neuroactive metabolites, the neurotoxins 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), and the neuroprotectant kynurenic acid (KYNA). In model systems in vitro and in vivo, 3-HK and QUIN have been shown to cause neurodegeneration via a combination of excitotoxic mechanisms and oxidative stress. Recent studies with HD patient samples and in HD model systems have supported the idea that a shift away from the synthesis of KYNA and towards the formation of 3-HK and QUIN may trigger the neuropathological features observed in HD. The enzyme kynurenine 3-monooxygenase (KMO) is located at a critical branching point in the KP such that inhibition of this enzyme by either pharmacological or genetic means shifts the flux in the pathway towards the formation of KYNA. This intervention ameliorates disease-relevant phenotypes in HD models. Here we review the work implicating the KP in HD pathology and discuss the potential of KMO as a therapeutic target for this disorder. As several neurodegenerative diseases exhibit alterations in KP metabolism, this concept has broader implications for the treatment of brain diseases.
Abstract Background Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway—which is implicated as dysfunctional in various psychiatric ...disorders—toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N -methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. Methods In the present study, we investigated adaptive—and possibly regulatory—changes in mice with a targeted deletion of Kmo ( Kmo –/– ) and characterized the kynurenine 3-monooxygenase–deficient mice using six behavioral assays relevant for the study of schizophrenia. Results Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo –/– mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo –/– mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo –/– mice showed potentiated horizontal activity in the open field paradigm. Conclusions Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.
The neurodegenerative disease Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the protein huntingtin (htt). Although the gene encoding htt was identified and cloned ...more than 15 years ago, and in spite of impressive efforts to unravel the mechanism(s) by which mutant htt induces nerve cell death, these studies have so far not led to a good understanding of pathophysiology or an effective therapy. Set against a historical background, we review data supporting the idea that metabolites of the kynurenine pathway (KP) of tryptophan degradation provide a critical link between mutant htt and the pathophysiology of HD. New studies in HD brain and genetic model organisms suggest that the disease may in fact be causally related to early abnormalities in KP metabolism, favoring the formation of two neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, over the related neuroprotective agent kynurenic acid. These findings not only link the excitotoxic hypothesis of HD pathology to an impairment of the KP but also define new drug targets and therefore have direct therapeutic implications. Thus, pharmacological normalization of the imbalance in brain KP metabolism may provide clinical benefits, which could be especially effective in early stages of the disease.
Protein misfolding is the molecular basis for several human diseases. How the primary amino acid sequence triggers misfolding and determines the benign or toxic character of the misfolded protein ...remains largely obscure. Among proteins that misfold, polyglutamine (polyQ) expansion proteins provide an interesting case: Each causes a distinct neurodegenerative disease that selectively affects different neurons. However, all are broadly expressed and most become toxic when the glutamine expansion exceeds approximately equal to 39 glutamine residues. The disease-causing polyQ expansion proteins differ profoundly in the amino acids flanking the polyQ region. We therefore hypothesized that these flanking sequences influence the specific toxic character of each polyQ expansion protein. Using a yeast model, we find that sequences flanking the polyQ region of human huntingtin exon I can convert a benign protein to a toxic species and vice versa. Further, we observe that flanking sequences can direct polyQ misfolding to at least two morphologically distinct types of polyQ aggregates. Very tight aggregates always are benign, whereas amorphous aggregates can be toxic. We thereby establish a previously undescribed systematic characterization of the influence of flanking amino acid sequences on polyQ toxicity.
The most conspicuous feature of many neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, is the occurrence of protein aggregates in ordered fibrillar structures ...known as amyloid found inside and outside of brain cells. The appearance of aggregates in diseased brains implies an underlying incapacity in the cellular machinery of molecular chaperones that normally functions to prevent the accumulation of misfolded proteins. Here we review recent studies that have revealed a critical role for molecular chaperones in several neurodegenerative disorders.
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