Neuroscience
Abstract
Synaptic plasticity is identified as innate to hypothalamic feeding circuits in their adaptation to the changing metabolic milieu in control of feeding and obesity. However, less is known about the regulatory principles of the dynamic changes of AgRP perikarya, a crucial region of the neuron gating excitation, and hence, feeding. Here we show that AgRP neurons activated either by food deprivation, ghrelin or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter, GABA, released by AgRP neurons that evoked this astrocytic response, which in turn, resulted in increased glial ensheetment of AgRP perikaryal by glial processes and increased excitability of AgRP neurons. We also identified that astrocyte-derived prostaglandin E2 directly activated, via EP2 receptors, AgRP neurons. Taken together, these observations unmasked a feedforward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding and overfeeding.
Authors
Luis Varela, Bernardo Stutz, Jae Eun Song, Jae Geun Kim, Zhong-Wu Liu, Xiao-Bing Gao, Tamas L. Horvath
Abstract
Opioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.
Authors
Gabriel D. Bosse, Roberto Cadeddu, Gabriele Floris, Ryan D. Farero, Eva Vigato, Suhjung J. Lee, Tejia Zhang, Nilesh W. Gaikwad, Kristen A. Keefe, Paul E.M. Phillips, Marco Bortolato, Randall T. Peterson
Abstract
BACKGROUND. Recently the α1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in Parkinson disease related to its function as the initial enzyme in ATP synthesis during glycolysis. An epidemiologic study of terazosin users showed a lower incidence of Parkinson disease when compared to users of tamsulosin, an α1 adrenergic receptor antagonist of a different class that does not activate PGK1. However, prior research on tamsulosin has suggested that it may in fact potentiate neurodegeneration, raising the question of whether it is an appropriate control group. METHODS. To address this question, we undertook an epidemiological study on Parkinson disease occurrence rate in 113,450 individuals from the U.S.A. with > 5 years of follow-up. Patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690) or controls matched on age, gender and Charlson Comorbidity Index score (n = 45,380). RESULTS. Incidence of Parkinson disease in tamsulosin users was 1.53%, which was significantly higher than that in both terazosin/alfuzosin/doxazosin users (1.10%; p<0.0001) and matched controls (1.01%; p < 0.0001). Terazosin/alfuzosin/doxazosin users did not differ in Parkinson disease risk from matched controls (p = 0.29). CONCLUSION. These results suggest that zosins may not confer a protective effect against Parkinson disease, but rather that tamsulosin may in some way potentiate Parkinson disease progression. FUNDING. This work was supported by Cerevel Therapeutics.
Authors
Rahul Sasane, Amy Bartels, Michelle Field, Maria I. Sierra, Sridhar Duvvuri, David L. Gray, Sokhom S. Pin, John J. Renger, David J. Stone
Abstract
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long-chain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit. Chloroquine increased expression of stearoyl-CoA desaturase-1 (scd1), the enzyme mediating fatty acid saturation status, suggesting that a shift towards mono-unsaturated fatty acids relieved toxicity. In human ALD fibroblasts chloroquine also increased SCD1 levels and reduced saturated VLCFAs. Conversely, pharmacological inhibition of SCD1 expression led to an increase in saturated VLCFAs, and CRISPR knockout of scd1 in zebrafish mimicked the motor phenotype of ALD zebrafish. Importantly, saturated VLCFAs caused ER stress in ALD fibroblasts whereas mono-unsaturated VLCFA did not. In parallel, we used liver X receptor (LXR) agonists to increase SCD1 expression, causing a shift from saturated towards mono-unsaturated VLCFA, and normalizing phospholipid profiles. Finally, Abcd1-/y mice receiving LXR agonist in their diet had VLCFA reductions in ALD-relevant tissues. These results suggest that metabolic rerouting of saturated to mono-unsaturated VLCFAs may alleviate lipid toxicity, a strategy that may be beneficial in ALD and other peroxisomal diseases in which VLCFAs play a key role.
Authors
Quentin Raas, Malu-Clair van de Beek, Sonja Forss-Petter, Inge M.E. Dijkstra, Abigail DeSchiffart, Briana C. Freshner, Tamara J. Stevenson, Yorrick R.J. Jaspers, Liselotte M. Nagtzaam, Ronald J.A. Wanders, Michel van Weeghel, Joo-Yeon Engelen-Lee, Marc Engelen, Florian Eichler, Johannes Berger, Joshua L. Bonkowsky, Stephan Kemp
Abstract
The excitability of interneurons requires Nav1.1, the α subunit of voltage-gated sodium channel. Nav1.1 deficiency and mutations reduce interneuron excitability, a major pathological mechanism for epilepsy syndromes. However, the regulatory mechanisms of Nav1.1 expression remain unclear. Here we provide evidence that neddylation is critical to Nav1.1 stability. Mutant mice lacking Nae1, an obligatory component of the E1 ligase for neddylation, in parvalbumin-positive interneurons (PVINs) exhibited spontaneous epileptic seizures and premature death. Electrophysiological studies indicate that Nae1 deletion reduced in PVIN excitability and GABA release, and consequently increased the network excitability of pyramidal neurons (PyNs). Further analysis revealed a reduction in sodium current density, not a change in channel property, in mutant PVINs and decreased Nav1.1 protein level. These results suggest that insufficient neddylation in PVINs reduces Nav1.1 stability and thus the excitability of PVINs; ensuing increased PyN activity causes seizures in mice. In agreement, Nav1.1 was found reduced by proteomic analysis that revealed abnormality in synapses and metabolic pathways. Our findings, for the first time, described a role of neddylation in maintaining Nav1.1 stability for PVIN excitability and reveal a new mechanism in pathogenesis of epilepsy.
Authors
Wenbing Chen, Bin Luo, Nannan Gao, Haiwen Li, Hongsheng Wang, Lei Li, Wanpeng Cui, Lei Zhang, Dong Sun, Fang Liu, Zhaoqi Dong, Xiao Ren, Hongsheng Zhang, Huabo Su, Wen-Cheng Xiong, Lin Mei
Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration
Abstract
Approximately 80% of neuromyelitis optica spectrum disorder (NMOSD) patients harbor serum anti–aquaporin-4 autoantibodies targeting astrocytes in the CNS. Crucial for NMOSD lesion initiation is disruption of the blood-brain barrier (BBB), which allows the entrance of Abs and serum complement into the CNS and which is a target for new NMOSD therapies. Astrocytes have important functions in BBB maintenance; however, the influence of their loss and the role of immune cell infiltration on BBB permeability in NMOSD have not yet been investigated. Using an experimental model of targeted NMOSD lesions in rats, we demonstrate that astrocyte destruction coincides with a transient disruption of the BBB and a selective loss of occludin from tight junctions. It is noteworthy that BBB integrity is reestablished before astrocytes repopulate. Rather than persistent astrocyte loss, polymorphonuclear leukocytes (PMNs) are the main mediators of BBB disruption, and their depletion preserves BBB integrity and prevents astrocyte loss. Inhibition of PMN chemoattraction, activation, and proteolytic function reduces lesion size. In summary, our data support a crucial role for PMNs in BBB disruption and NMOSD lesion development, rendering their recruitment and activation promising therapeutic targets.
Authors
Anne Winkler, Claudia Wrzos, Michael Haberl, Marie-Theres Weil, Ming Gao, Wiebke Möbius, Francesca Odoardi, Dietmar R. Thal, Mayland Chang, Ghislain Opdenakker, Jeffrey L. Bennett, Stefan Nessler, Christine Stadelmann
Abstract
The coronavirus disease 2019 (COVID-19) rapidly progressed to a global pandemic. Although patients totally recover from COVID-19 pneumonia, long-term effects on the brain still need to be explored. Here, two subtypes (mild type-MG and severe type-SG) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI three months after discharge were recruited. Changes in gray matter morphometry, cerebral blood flow (CBF) and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measurements and inflammation markers were further analyzed. Compared with healthy controls, the decrease in cortical thickness/CBF, and the changes in WM microstructure were observed to be more severe in the SG than MG, especially in the frontal and limbic systems. Furthermore, changes in brain microstructure, CBF and tracts parameters were significantly correlated with inflammatory markers. The indirect injury related to inflammatory storm may damage the brain, that led to these interesting observations. There are also other likely potential causes, such as hypoxemia and dysfunction of vascular endothelium, et al. The abnormalities in these brain areas need to be monitored in the process of complete recovery, which could help clinicians to understand the potential neurological sequelae of COVID-19.
Authors
Yuanyuan Qin, Jinfeng Wu, Tao Chen, Jia Li, Guiling Zhang, Di Wu, Yiran Zhou, Ning Zheng, Aoling Cai, Qin Ning, Anne Manyande, Fuqiang Xu, Jie Wang, Wenzhen Zhu
Abstract
The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain; investigation into their mode of action is essential for ongoing clinical development. A3ARs on immune cells, and their activation during pathology, modulates cytokine release. Thus, immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing but unknown. Studies herein discovered that RagKO mice lacking T- and B-cells are insensitive to the anti-allodynic effects of A3AR agonists versus wild-type (WT) mice. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T-cells (CD4+-T) from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in RagKO mice; CD4+-T from Adora3KO or Il10KO mice did not. Transfer of CD4+-T from WT, but not Il10KO, into Il10KO mice fully reinstated anti-allodynic effects of A3AR activation. Transfer of CD4+-T from WT, but not Il10KO, into Adora3KO mice fully reinstated anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when co-cultured with CD4+-T in an IL-10-dependent manner. A3AR actions on CD4+-T infiltrate in the DRG decreased phosphorylation of GluN2B-containing N‐methyl‐D‐aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+-T cells to release of IL-10 is required and sufficient for A3AR agonists as therapeutics.
Authors
Mariaconcetta Durante, Silvia Squillace, Filomena Lauro, Luigino Antonio Giancotti, Elisabetta Coppi, Federica Cherchi, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Grant Kolar, Carrie Wahlman, Adeleye Opejin, Cuiying Xiao, Marc L. Reitman, Dilip K. Tosh, Daniel Hawiger, Kenneth A. Jacobson, Daniela Salvemini
Abstract
Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.
Authors
Leslie A. Sandusky-Beltran, Andrii Kovalenko, Devon S. Placides, Kevin Ratnasamy, Chao Ma, Jerry B. Hunt Jr., Huimin Liang, John Ivan T. Calahatian, Camilla Michalski, Margaret Fahnestock, Laura J. Blair, April L. Darling, Jeremy D. Baker, Sarah N. Fontaine, Chad A. Dickey, Joshua J. Gamsby, Kevin R. Nash, Erin Abner, Maj-Linda B. Selenica, Daniel C. Lee
Abstract
Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-β superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects — concordant with SPR results — on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.
Authors
Jia Li, Maureen Fredericks, Marishka Cannell, Kathryn Wang, Dianne Sako, Michelle C. Maguire, Rosa Grenha, Katia Liharska, Lavanya Krishnan, Troy Bloom, Elitza P. Belcheva, Pedro A. Martinez, Roselyne Castonguay, Sarah Keates, Mark J. Alexander, Hyunwoo Choi, Asya V. Grinberg, R. Scott Pearsall, Paul Oh, Ravindra Kumar, Rajasekhar N.V.S. Suragani
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)