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Robert Schwarcz - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Quinolinic Acid by 3‐Hydroxyanthranilic Acid Oxygenase in Rat Brain Tissue In Vitro
Journal of neurochemistry, 2006Co-Authors: Alan C. Foster, Robert J. White, Robert SchwarczAbstract:In mammalian peripheral organs, 3-Hydroxyanthranilic Acid oxygenase (3HAO), catalyzing the conversion of 3-Hydroxyanthranilic Acid to quinolinic Acid, constitutes a link in the catabolic pathway of tryptophan to NAD. Because of the possible involvement of quinolinic Acid in the initiation of neurodegenerative phenomena, we examined the presence and characteristics of 3HAO in rat brain tissue. A simple and sensitive assay method, based on the use of [carboxy-14C]3-Hydroxyanthranilic Acid as a substrate, was developed and the enzymatic product, [14C]quinolinic Acid, identified by chromatographic and biochemical means. Kinetic analysis of rat forebrain 3HAO revealed a Km of 3.6 +/- 0.5 microM for 3-Hydroxyanthranilic Acid and a Vmax of 73.7 +/- 9.5 pmol quinolinic Acid/h/mg tissue. The enzyme showed pronounced selectivity for its substrate, since several substances structurally and metabolically related to 3-Hydroxyanthranilic Acid caused less than 25% inhibition of activity at 500 microM. Both the Fe2+ dependency and the distinct subcellular distribution (soluble fraction) of brain 3HAO indicated a close resemblance to 3HAO from peripheral tissues. Examination of the regional distribution in the brain demonstrated a 10-fold variation between the region of highest (olfactory bulb) and lowest (retina) 3HAO activity. The brain enzyme was present at the earliest age tested (7 days postnatum) and increased to 167% at 15 days before reaching adult levels. Enzyme activity was stable over extended periods of storage at -80 degrees C. Taken together, these data indicate that measurements of brain 3HAO may yield significant information concerning a possible role of quinolinic Acid in brain function and/or dysfunction.
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3-Hydroxyanthranilic Acid accumulation following administration of the 3-Hydroxyanthranilic Acid 3,4-dioxygenase inhibitor NCR-631.
European journal of pharmacology, 1999Co-Authors: Bodil Fornstedt-wallin, Robert Schwarcz, Jan Lundström, Göran Fredriksson, Johan LuthmanAbstract:Abstract In the kynurenine pathway of tryptophan metabolism, 3-Hydroxyanthranilic Acid is the substrate for formation of the excitotoxin quinolinic Acid by 3-Hydroxyanthranilic Acid 3,4-dioxygenase. This study was designed to characterize the effects on 3-Hydroxyanthranilic Acid after treatment with the 3-Hydroxyanthranilic Acid 3,4-dioxygenase inhibitor 4,6-di-bromo-3-Hydroxyanthranilic Acid (NCR-631) in Sprague–Dawley rats. The blood plasma and brain concentrations of 3-Hydroxyanthranilic Acid were found to increase rapidly in a dose-dependent manner after gavage administration of NCR-631. However, the effect was relatively transient, with a decline in 3-Hydroxyanthranilic Acid levels already at 1h after NCR-631 treatment. Similar increases in plasma levels of 3-Hydroxyanthranilic Acid were observed following either gavage or parenteral (i.v. or s.c.) administration of NCR-631 (25 mg/kg). Only a minor enhancement of the NCR-631-induced increase in plasma 3-Hydroxyanthranilic Acid levels was found after sub-chronic treatment (25 mg/kg by gavage; 7 days, b.i.d.), suggesting a low propensity for altered 3-Hydroxyanthranilic Acid 3,4-dioxygenase activity following repeated inhibition. Administration of [ 14 C]NCR-631 suggested 20 min initial plasma half life and an oral absorption around 50%. A dose of 250 mg/kg [ 14 C]NCR-631 given by gavage provided plasma levels of almost 2 μmol/ml and a brain concentration of approximately 16 nmol/g, when analyzed 15 min after administration. Neither acute nor sub-chronic administration of NCR-631 caused any substantial effects on quinolinic Acid levels in plasma or brain. Also, the plasma levels of kynurenic Acid, another neuroactive kynurenine pathway metabolite, were unaffected by acute NCR-631 treatment. Moreover, the brain levels of the major cerebral tryptophan metabolites 5-hydroxytryptamine and 5-hydroxyindoleacetic Acid remained unchanged following administration of NCR-631. Although reversible inhibition of 3-Hydroxyanthranilic Acid 3,4-dioxygenase with NCR-631 in normal rats is insufficient to cause substantial changes in the levels of quinolinic Acid or other important tryptophan metabolites, it causes a major accumulation of the substrate 3-Hydroxyanthranilic Acid.
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Synthesis and QSAR of substituted 3-Hydroxyanthranilic Acid derivatives as inhibitors of 3-Hydroxyanthranilic Acid dioxygenase (3-HAO)
European Journal of Medicinal Chemistry, 1999Co-Authors: Linderberg M, Robert Schwarcz, Johan Luthman, Sven Hellberg, Bjork Susanna Karin Maria, Gotthammar Kristina Brigitta, Thomas Högberg, Persson Kerstin Margareta Irma, Rolf JohanssonAbstract:Novel 4,5-, 4,6-disubstituted and 4,5,6-trisubstituted 3-Hydroxyanthranilic Acid derivatives were synthesized and their ability to reduce the production of the excitotoxin quinolinic Acid (QUIN) by inhibition of brain 3-Hydroxyanthranilic Acid dioxygenase (3-HAO) was subsequently investigated. The potency of the compounds to inhibit 3-HAO was assayed in rat brain homogenate, while chemical stability of certain compounds was studied by HPLC. The data were used to generate quantitative structure-activity relationship (QSAR) models for potency of 3-HAO inhibition and compound stability. Compounds with longer half-lives were obtained when the difference between the HOMO and LUMO was increased, while electron withdrawing groups in the 4- and 5-positions increased the potency of 3-HAO inhibition. Selected compounds that showed high potency in vitro were also found to be efficacious inhibitors in vivo after cerebral administration in rats.
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3-Hydroxyanthranilic Acid oxygenase-containing astrocytic processes surround glutamate-containing axon terminals in the rat striatum
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1995Co-Authors: Rosalinda C. Roberts, Etsuo Okuno, Kathleen E. Mccarthy, Op Ottersen, Robert SchwarczAbstract:Glutamate, the major transmitter of the corticostriatal pathway, is present in abundance in the striatum. 3-Hydroxyanthranilic Acid oxygenase (3HAO) is the biosynthetic enzyme for quinolinic Acid, an endogenous agonist of the NMDA glutamate receptor subtype and a potent neurotoxin. In order to explore the anatomical basis of possible functional interactions between glutamate and quinolinic Acid in the rat striatum, pre- and postembedding immunocytochemical methods were used to localize 3HAO immunoreactivity (-i) and glutamate-i at the electron microscopic level. In accordance with previous light microscopic and biochemical studies, 3HAO-i was detected exclusively in astrocytes throughout the striatum. Notably, 3HAO-i was present in fine- caliber glial processes that often surrounded or abutted synaptic profiles, both asymmetric and symmetric. Glutamate-i was heavily deposited (3–13-fold higher gold particle density than tissue average) in axon terminals forming asymmetric synapses with spines and, occasionally, dendrites. In contrast, terminals forming symmetric synapses, dendrites, neuronal somata, and glial cells contained significantly less labeling than terminals forming asymmetric synapses. In double-labeled material, 3HAO-i was observed in glial processes that partially surrounded or were adjacent to glutamate-labeled terminals forming asymmetric synapses. 3HAO-labeled glial processes were also adjacent to unlabeled terminals forming symmetric synapses. Since quinolinic Acid is known to enter the extracellular compartment readily, these results suggest that astrocytic quinolinic Acid may participate in the regulation of glutamatergic neurotransmission in the rat striatum.
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Immunocytochemical localization of the quinolinic Acid synthesizing enzyme, 3-Hydroxyanthranilic Acid oxygenase, in the rat substantia nigra.
Brain research, 1994Co-Authors: Rosalinda C. Roberts, Etsuo Okuno, Kathleen E. Mccarthy, Robert SchwarczAbstract:Quinolinic Acid, an endogenous excitatory amino Acid receptor agonist, may play a role in several brain diseases. In the present study, the immunocytochemical localization of 3-Hydroxyanthranilic Acid oxygenase (3HAO), the enzyme responsible for the synthesis of quinolinic Acid, was examined in the adult rat substantia nigra at the light and electron microscopic levels. 3HAO-immunoreactivity was detected exclusively in astrocytes. Labeling was present in cell bodies and in fine glial processes, which frequently encircled capillaries and partially enveloped neuronal somata. Notably, 3HAO-labeled processes were in close contact with several types of synaptic profiles. Often, they partially engulfed asymmetric synapses, characteristic of excitatory neurotransmission. In addition, they were found in apposition to putative dopaminergic cell bodies. These data provide an anatomical basis for the idea that functional interactions may occur between glial processes which synthesize quinolinic Acid, and synaptic profiles, many of which presumably utilize excitatory neurotransmitters.
Xuehong Zhang - One of the best experts on this subject based on the ideXlab platform.
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Genetic Engineering of Pseudomonas Chlororaphis Lzh-T5 to Enhance Production of Trans-2,3-Dihydro-3-Hydroxyanthranilic Acid
2020Co-Authors: Xuehong Zhang, Wei Wang, Yujie Huang, Ruiming Wang, Tengfei Wang, Kaiquan LiuAbstract:Abstract Background: Trans-2,3-dihydro-3-Hydroxyanthranilic Acid (DHHA) is a cyclic β-amino Acid used for the synthesis of non-natural peptides and chiral materials. It is an intermediate product of phenazine production in Pseudomonas spp . Lzh-T5 is a P. chlororaphis strain isolated from tomato rhizosphere found in China. It can synthesize three antifungal phenazine compounds. Results: Disrupting the phzF gene of P. chlororaphis Lzh-T5 results in DHHA accumulation. Several strategies were used to improve production of DHHA: enhancing the shikimate pathway by overexpression, knocking out negative regulatory genes, and adding metal ions to the medium. In this study, three regulatory genes ( psrA , pykF, and rpeA ) were-disrupted in the genome of P. chlororaphis Lzh-T5, yielding 4.55 g/L of DHHA. When six key genes selected from the shikimate, pentose phosphate, and gluconeogenesis pathways were overexpressed, the yield of DHHA increased to 6.89g/L. Fe 3+ was added to the medium for DHHA fermentation. This genetically engineered strain increased the DHHA production to 10.45g/L. Conclusions: P. chlororaphis Lzh-T5 could be modified as a microbial factory to produce DHHA by inactivating phzF , disrupting negative regulatory genes, overexpressing key genes, and adding metal ions to medium for fermentation.
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Production of trans-2,3-dihydro-3-Hydroxyanthranilic Acid by engineered Pseudomonas chlororaphis GP72
Applied microbiology and biotechnology, 2017Co-Authors: Li Yifan, Kaiquan Liu, Jia Zhao, Wei Wang, Xuehong ZhangAbstract:Trans-2,3-dihydro-3-Hydroxyanthranilic Acid (DHHA) is a cyclic β-amino Acid that can be used for the synthesis of chiral materials and nonnatural peptides. The aim of this study was to accumulate DHHA by engineering Pseudomonas chlororaphis GP72, a nonpathogenic strain that produces phenazine-1-carboxylic Acid and 2-hydroxyphenazine. First, the phzF deletion mutant DA1 was constructed, which produced 1.91 g/L DHHA. Moreover, rpeA and pykF were disrupted and then ppsA and tktA were co-expressed in strain DA1. The resulting strain DA4 increased DHHA concentration to 4.98 g/L, which is 2.6-fold than that of DA1. The effects of the addition of glucose, glycerol, l-tryptophan, and Fe3+on DHHA production were also investigated. Strain DA4 produced 7.48 g/L of DHHA in the culture medium in the presence of 12 g/L glucose and 3 mM Fe3+, which was 1.5-fold higher than the strain in the original fermentation conditions. These results indicate the potential of P. chlororaphis GP72 as a DHHA producer.
Roger J.w. Truscott - One of the best experts on this subject based on the ideXlab platform.
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Involvement of tyrosine residues in the tanning of proteins by 3-Hydroxyanthranilic Acid.
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Michael K. Manthey, Stephen G. Pyne, Roger J.w. TruscottAbstract:The binding of oxidized phenolic compounds to proteins is of importance in a number of biological systems, including the sclerotization of insect cuticle and the tanning of cocoons. 3-Hydroxyanthranilic Acid (3HAA), an aminophenol, is a tryptophan metabolite that undergoes autoxidation readily, and proteins incubated in the presence of 3HAA and oxygen become colored and oxidized. Some moth species are thought to employ this reactivity of 3HAA with proteins for the tanning of cocoons, but the detailed mechanism of this process has not been studied previously. We show that one reaction pathway involves the covalent coupling of 3HAA with tyrosine to form a benzocoumarin derivative, a dibenzo[b,d]pyran-6-one. The stability of the benzocoumarin to conditions of Acid hydrolysis normally used for protein digestion has enabled the isolation of the tyrosine adduct from bovine serum albumin that had been incubated with 3HAA. The adduct was also isolated from cocoons of Samia cynthia and Hyalophora gloveri, two species of moths reported to utilize 3HAA for cocoon tanning. These findings indicate that one mechanism of interaction of 3HAA with proteins involves a radical-radical coupling with tyrosine residues.
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Modification of proteins by 3-Hydroxyanthranilic Acid: The role of lysine residues
Archives of biochemistry and biophysics, 1991Co-Authors: M.graciela Benavente, Roger J.w. TruscottAbstract:Abstract The mechanism of reaction of proteins with 3-Hydroxyanthranilic Acid (3OHA) under oxidizing conditions has been examined. A range of proteins were found to tan when exposed to oxidized 3OHA. One exception was lysozyme which tanned only after being denatured by reduction and carboxymethylation. Chemical modification experiments using bovine serum albumin (BSA) suggested that lysine was the primary site of reaction in 3OHA-mediated protein tanning. This reactivity of 3OHA toward lysine was confirmed by autoxidizing 3OHA in the presence of amino Acid homopolymers. The rate of modification of both BSA and polylysine was pH dependent. At neutral pH, a component of the coloration of the protein was found to be due to the formation of a lysyl-p-quinone adduct. Other products appear to arise through addition to the 3OHA quinone imine. Poly(Glu,Lys) was tanned by 3OHA at a greatly reduced rate, suggesting that electrostatic interactions may influence the reaction with lysine residues and may provide an explanation for the lack of tanning of lysozyme. Despite the reaction between 3OHA and lysine, amino Acid analysis revealed little quantitative change in the lysine content of proteins even after exposure to 3OHA for a period of 24 h. These results support the proposal that reaction with lysine residues is the major route of protein tanning by 3-Hydroxyanthranilic Acid.
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Triphenodioxazine-1,8-dicarboxylic Acid as an oxidation product of 3-Hydroxyanthranilic Acid
Journal of Heterocyclic Chemistry, 1991Co-Authors: Larry A. Hick, Michael K. Manthey, Roger J.w. TruscottAbstract:The oxidation of 3-Hydroxyanthranilic Acid (30HA) 1 by aqueous buffered potassium ferricyanide produces a number of coloured compounds. These include cinnabarinic Acid 2 (yellow), a p-quinone dimer 3 (red) and 9-carboxy-2-hydroxy-3H-phenoxazin-3-one 4 (brown). Also present by tlc is a bright pink compound. The structure of this compound has been demonstrated to be triphenodioxazine-1,8-dicarboxylic Acid 5a.
C Oberg - One of the best experts on this subject based on the ideXlab platform.
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Effects of the 3-Hydroxyanthranilic Acid analogue NCR-631 on anoxia-, IL-1 beta- and LPS-induced hippocampal pyramidal cell loss in vitro.
Amino acids, 1998Co-Authors: J Luthman, A C Radesäter, C ObergAbstract:The kynurenine pathway intermediate 3-Hydroxyanthranilic Acid (3-HANA) is converted by 3-HANA 3,4-dioxygenase (3-HAO) to the putative neuropathogen quinolinic Acid (QUIN). In the present study, the neuroprotective effects of the 3-HANA analogue and 3-HAO inhibitor NCR-631 was investigated using organotypic cultures of rat hippocampus. An anoxic lesion was induced by exposing the cultures to 100% N2 for 150 min, resulting in a pronounced loss of pyramidal neurons, as identified using NMDA-R1 receptor subunit immunohistochemistry. NCR-631 provided a concentration-dependent protective effect against the anoxia. NCR-631 was also found to counteract the loss of pyramidal neurons in two models of neuroinflammatory-related damage; incubation with either LPS (10 ng/ml) or IL-1 beta (10 IU/ml). The findings suggest that NCR-631 has neuroprotective properties and that it may be a useful tool to study the role of kynurenines in neurodegeneration.
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Effects of the 3-Hydroxyanthranilic Acid analogue NCR-631 on anoxia-, IL-1 beta- and LPS-induced hippocampal pyramidal cell loss in vitro.
Amino Acids, 1998Co-Authors: Johan Luthman, A C Radesäter, C ObergAbstract:The kynurenine pathway intermediate 3-Hydroxyanthranilic Acid (3-HANA) is converted by 3-HANA 3,4-dioxygenase (3-HAO) to the putative neuropathogen quinolinic Acid (QUIN). In the present study, the neuroprotective effects of the 3-HANA analogue and 3-HAO inhibitor NCR-631 was investigated using organotypic cultures of rat hippocampus. An anoxic lesion was induced by exposing the cultures to 100% N2 for 150 min, resulting in a pronounced loss of pyramidal neurons, as identified using NMDA-R1 receptor subunit immunohistochemistry. NCR-631 provided a concentration-dependent protective effect against the anoxia. NCR-631 was also found to counteract the loss of pyramidal neurons in two models of neuroinflammatory-related damage; incubation with either LPS (10 ng/ml) or IL-1β (10 IU/ml). The findings suggest that NCR-631 has neuroprotective properties and that it may be a useful tool to study the role of kynurenines in neurodegeneration.
Johan Luthman - One of the best experts on this subject based on the ideXlab platform.
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Anticonvulsant effects of the 3-Hydroxyanthranilic Acid dioxygenase inhibitor NCR-631
Amino acids, 2000Co-Authors: Johan LuthmanAbstract:The kynurenine pathway intermediate 3-Hydroxyanthranilic Acid (3-HANA) is converted by 3-HANA 3,4-dioxygenase (3-HAO) to the pro-convulsive excitotoxin quinolinic Acid. In the present study, the anticonvulsant effect of the 3-HAO inhibitor NCR-631 was investigated in models of chemically- and sound-induced seizures. Administration of NCR-631 i.c.v. at a dose of 300 nmol in Sprague-Dawley rats was found to prolong the latency of occurrence of pentylenetetrazole (PTZ)-induced seizures. Also systemic pre-treatment with NCR-631 s.c. in N.M.R.I. mice subjected to PTZ-induced seizures provided an increase in the latency until onset of seizures, concomitant with a reduction in the severity of the seizures. However, the anticonvulsant effect of NCR-631 was short lasting (15–30 min), and only observed at a dose of 250 mg/kg. A similar dose- and time-dependent anticonvulsant effect of NCR-631 was found in seizure-prone DBA/2J mice following sound-induced convulsions. Hence, the findings show that NCR-631 has anticonvulsant properties against generalized tonic-clonic seizures of different origin, suggesting that it may constitute a useful tool to study the role of kynurenines in various convulsive states.
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3-Hydroxyanthranilic Acid accumulation following administration of the 3-Hydroxyanthranilic Acid 3,4-dioxygenase inhibitor NCR-631.
European journal of pharmacology, 1999Co-Authors: Bodil Fornstedt-wallin, Robert Schwarcz, Jan Lundström, Göran Fredriksson, Johan LuthmanAbstract:Abstract In the kynurenine pathway of tryptophan metabolism, 3-Hydroxyanthranilic Acid is the substrate for formation of the excitotoxin quinolinic Acid by 3-Hydroxyanthranilic Acid 3,4-dioxygenase. This study was designed to characterize the effects on 3-Hydroxyanthranilic Acid after treatment with the 3-Hydroxyanthranilic Acid 3,4-dioxygenase inhibitor 4,6-di-bromo-3-Hydroxyanthranilic Acid (NCR-631) in Sprague–Dawley rats. The blood plasma and brain concentrations of 3-Hydroxyanthranilic Acid were found to increase rapidly in a dose-dependent manner after gavage administration of NCR-631. However, the effect was relatively transient, with a decline in 3-Hydroxyanthranilic Acid levels already at 1h after NCR-631 treatment. Similar increases in plasma levels of 3-Hydroxyanthranilic Acid were observed following either gavage or parenteral (i.v. or s.c.) administration of NCR-631 (25 mg/kg). Only a minor enhancement of the NCR-631-induced increase in plasma 3-Hydroxyanthranilic Acid levels was found after sub-chronic treatment (25 mg/kg by gavage; 7 days, b.i.d.), suggesting a low propensity for altered 3-Hydroxyanthranilic Acid 3,4-dioxygenase activity following repeated inhibition. Administration of [ 14 C]NCR-631 suggested 20 min initial plasma half life and an oral absorption around 50%. A dose of 250 mg/kg [ 14 C]NCR-631 given by gavage provided plasma levels of almost 2 μmol/ml and a brain concentration of approximately 16 nmol/g, when analyzed 15 min after administration. Neither acute nor sub-chronic administration of NCR-631 caused any substantial effects on quinolinic Acid levels in plasma or brain. Also, the plasma levels of kynurenic Acid, another neuroactive kynurenine pathway metabolite, were unaffected by acute NCR-631 treatment. Moreover, the brain levels of the major cerebral tryptophan metabolites 5-hydroxytryptamine and 5-hydroxyindoleacetic Acid remained unchanged following administration of NCR-631. Although reversible inhibition of 3-Hydroxyanthranilic Acid 3,4-dioxygenase with NCR-631 in normal rats is insufficient to cause substantial changes in the levels of quinolinic Acid or other important tryptophan metabolites, it causes a major accumulation of the substrate 3-Hydroxyanthranilic Acid.
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Synthesis and QSAR of substituted 3-Hydroxyanthranilic Acid derivatives as inhibitors of 3-Hydroxyanthranilic Acid dioxygenase (3-HAO)
European Journal of Medicinal Chemistry, 1999Co-Authors: Linderberg M, Robert Schwarcz, Johan Luthman, Sven Hellberg, Bjork Susanna Karin Maria, Gotthammar Kristina Brigitta, Thomas Högberg, Persson Kerstin Margareta Irma, Rolf JohanssonAbstract:Novel 4,5-, 4,6-disubstituted and 4,5,6-trisubstituted 3-Hydroxyanthranilic Acid derivatives were synthesized and their ability to reduce the production of the excitotoxin quinolinic Acid (QUIN) by inhibition of brain 3-Hydroxyanthranilic Acid dioxygenase (3-HAO) was subsequently investigated. The potency of the compounds to inhibit 3-HAO was assayed in rat brain homogenate, while chemical stability of certain compounds was studied by HPLC. The data were used to generate quantitative structure-activity relationship (QSAR) models for potency of 3-HAO inhibition and compound stability. Compounds with longer half-lives were obtained when the difference between the HOMO and LUMO was increased, while electron withdrawing groups in the 4- and 5-positions increased the potency of 3-HAO inhibition. Selected compounds that showed high potency in vitro were also found to be efficacious inhibitors in vivo after cerebral administration in rats.
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Effects of the 3-Hydroxyanthranilic Acid analogue NCR-631 on anoxia-, IL-1 beta- and LPS-induced hippocampal pyramidal cell loss in vitro.
Amino Acids, 1998Co-Authors: Johan Luthman, A C Radesäter, C ObergAbstract:The kynurenine pathway intermediate 3-Hydroxyanthranilic Acid (3-HANA) is converted by 3-HANA 3,4-dioxygenase (3-HAO) to the putative neuropathogen quinolinic Acid (QUIN). In the present study, the neuroprotective effects of the 3-HANA analogue and 3-HAO inhibitor NCR-631 was investigated using organotypic cultures of rat hippocampus. An anoxic lesion was induced by exposing the cultures to 100% N2 for 150 min, resulting in a pronounced loss of pyramidal neurons, as identified using NMDA-R1 receptor subunit immunohistochemistry. NCR-631 provided a concentration-dependent protective effect against the anoxia. NCR-631 was also found to counteract the loss of pyramidal neurons in two models of neuroinflammatory-related damage; incubation with either LPS (10 ng/ml) or IL-1β (10 IU/ml). The findings suggest that NCR-631 has neuroprotective properties and that it may be a useful tool to study the role of kynurenines in neurodegeneration.
