List of publications for the week of November 16, 2021
IL-4 expressing cells are recruited to nerve after injury and promote regeneration
(2022) Experimental Neurology, 347, art. no. 113909, .
Pan, D., Schellhardt, L., Acevedo-Cintron, J.A., Hunter, D., Snyder-Warwick, A.K., Mackinnon, S.E., Wood, M.D.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Interleukin-4 (IL-4) has garnered interest as a cytokine that mediates regeneration across multiple tissues including peripheral nerve. Within nerve, we previously showed endogenous IL-4 was critical to regeneration across nerve gaps. Here, we determined a generalizable role of IL-4 in nerve injury and regeneration. In wild-type (WT) mice receiving a sciatic nerve crush, IL-4 expressing cells preferentially accumulated within the injured nerve compared to affected sites proximal, such as dorsal root ganglia (DRGs), or distal muscle. Immunohistochemistry and flow cytometry confirmed that eosinophils (CD45+, CD11b+, CD64−, Siglec-F+) were sources of IL-4 expression. Examination of targets for IL-4 within nerve revealed macrophages, as well as subsets of neurons expressed IL-4R, while Schwann cells expressed limited IL-4R. Dorsal root ganglia cultures were exposed to IL-4 and demonstrated an increased proportion of neurons that extended axons compared to cultures without IL-4 (control), as well as longer myelinated axons compared to cultures without IL-4. The role of endogenous IL-4 during nerve injury and regeneration in vivo was assessed following a sciatic nerve crush using IL-4 knockout (KO) mice. Loss of IL-4 affected macrophage accumulation within injured nerve compared to WT mice, as well as shifted macrophage phenotype towards a CD206- phenotype with altered gene expression. Furthermore, this loss of IL-4 delayed initial axon regeneration from the injury crush site and subsequently delayed functional recovery and re-innervation of neuromuscular junctions compared to wild-type mice. Given the role of endogenous IL-4 in nerve regeneration, exogenous IL-4 was administered daily to WT mice following a nerve crush to examine regeneration. Daily IL-4 administration increased early axonal extension and CD206+ macrophage accumulation but did not alter functional recovery compared to untreated mice. Our data demonstrate IL-4 promotes nerve regeneration and recovery after injury. © 2021 Elsevier Inc.
Author Keywords
Functional recovery; IL-4; Interleukin; Macrophage; Nerve crush; Nerve regeneration; Peripheral nerve
Funding details
National Institutes of HealthNIHK08NS096232, R01 NS086773, R01 NS115960
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior(2021) Translational Psychiatry, 11 (1), art. no. 570, .
Gomez, J.L.a , Bonaventura, J.a , Keighron, J.b , Wright, K.M.a , Marable, D.L.a , Rodriguez, L.A.a , Lam, S.a , Carlton, M.L.a , Ellis, R.J.a , Jordan, C.J.c , Bi, G.-H.c , Solis, O.a , Pignatelli, M.d , Bannon, M.J.e , Xi, Z.-X.c , Tanda, G.b , Michaelides, M.a f
a Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, United States
b Medication Development Program, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, United States
c Addiction Biology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, United States
d Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO 63110, United States
e Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, United States
f Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
Abstract
Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+ were dependent on the Zn2+ transporter 3 (ZnT3), a neuronal Zn2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+ deficiency in mice resulted in decreased striatal Zn2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+ release and turnover/metabolism in the striatum, and that synaptically released Zn2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn2+ may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
Funding details
National Institutes of HealthNIH
U.S. Department of EnergyUSDOEDE-FG02-92ER14244
National Institute on Drug AbuseNIDADA000069, DA000611
Document Type: Article
Publication Stage: Final
Source: Scopus
Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
(2021) Nature Communications, 12 (1), art. no. 6321, .
Mahlokozera, T.a , Patel, B.a , Chen, H.a , Desouza, P.a , Qu, X.a , Mao, D.D.a , Hafez, D.a , Yang, W.b , Taiwo, R.a , Paturu, M.a , Salehi, A.a , Gujar, A.D.a , Dunn, G.P.a c d , Mosammaparast, N.c , Petti, A.A.a d e , Yano, H.a b d e , Kim, A.H.a b d e f
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
e Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance. © 2021, The Author(s).
Funding details
National Institutes of HealthNIHP30 CA091842, R01 NS106612, R01 NS111014, R01NS051255, S10OD021629-01A1, S10OD027042
National Institute of Neurological Disorders and StrokeNINDSR01 NS094670
Foundation for Barnes-Jewish Hospital
Alvin J. Siteman Cancer Center
Document Type: Article
Publication Stage: Final
Source: Scopus
TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy
(2021) Science Advances, 7 (45), art. no. eabg3897, .
Alquezar, C.a , Schoch, K.M.b , Geier, E.G.c , Ramos, E.M.d , Scrivo, A.e , Li, K.H.f , Argouarch, A.R.a , Mlynarski, E.E.g , Dombroski, B.g , DeTure, M.h , Dickson, D.W.h , Yokoyama, J.S.c , Cuervo, A.M.e , Burlingame, A.L.f , Schellenberg, G.D.g , Miller, T.M.b , Miller, B.L.a , Kao, A.W.a
a UCSF Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA 94158, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Depart-ment of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, United States
d Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, United States
e Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, United States
f Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, United States
g Department of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4238, United States
h Depart-ment of Neuroscience, The Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, United States
Abstract
Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions are known as tauopathies. We previously linked a loss-of-function mutation in the TSC1 gene to tau accumulation and frontotemporal lobar degeneration. Now, we have identified genetic variants in TSC1 that decrease TSC1/hamartin levels and predispose to tauopathies such as Alzheimer’s disease and progressive supranuclear palsy. Cellular and murine models of TSC1 haploinsufficiency, as well as human brains carrying a TSC1 risk variant, accumulated tau protein that exhibited aberrant acetylation. This acetylation hindered tau degradation via chaperone-mediated autophagy, thereby leading to its accumulation. Aberrant tau acetylation in TSC1 haploinsufficiency resulted from the dysregulation of both p300 acetyltransferase and SIRT1 deacetylase. Pharmacological modulation of either enzyme restored tau levels. This study substantiates TSC1 as a novel tauopathy risk gene and includes TSC1 haploinsufficiency as a genetic model for tauopathies. In addition, these findings promote tau acetylation as a rational target for tauopathy therapeutics and diagnostic. Copyright © 2021 The Authors, some rights reserved;
Document Type: Article
Publication Stage: Final
Source: Scopus
The addiction risk factor: A unitary genetic vulnerability characterizes substance use disorders and their associations with common correlates
(2021) Neuropsychopharmacology, .
Hatoum, A.S.a , Johnson, E.C.a , Colbert, S.M.C.a , Polimanti, R.b c , Zhou, H.b c , Walters, R.K.d e , Gelernter, J.b c f g , Edenberg, H.J.h i , Bogdan, R.j , Agrawal, A.a
a Washington University School of Medicine, Department of Psychiatry, Saint Louis, MO, United States
b Department of Psychiatry, Division of Human Genetics, Yale School of Medicine, New Haven, CT, United States
c Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
d Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
e Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
f Department of Genetics, Yale School of Medicine, New Haven, CT, United States
g Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
h Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
i Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
j Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modeling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance-specific Ns range: 82,707–435,563) while adjusting for the genetics of substance use (Ns = 184,765−632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk-taking, executive function, neuroticism; Ns = 328,339−427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk-taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for the genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. © 2021, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.
Funding details
National Institute of Mental HealthNIMH
National Institute on Drug AbuseNIDA
U.S. Department of Veterans AffairsVA
Office of Research and DevelopmentORD
Health Services Research and DevelopmentHSR&D
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Depression and Inflammatory Markers in Veterans With Multiple Sclerosis
(2021) Biological Research for Nursing, .
Newland, P.a , Basan, Y.a , Chen, L.b , Wu, G.b
a Goldfarb School of Nursing at Barnes-Jewish College, Saint Louis, MO, United States
b Washington University in St Louis, Saint Louis, MO, United States
Abstract
Multiple sclerosis (MS), an inflammatory neurodegenerative disease of the central nervous system (CNS), afflicts over one per thousand people in the United States. The pathology of MS typically involves lesions in several regions, including the brain and spinal cord. The manifestation of MS is variable and carries great potential to negatively impact quality of life (QOL). Evidence that inflammatory markers are related to depression in MS is accumulating. However, there are barriers in precisely identifying the biological mechanisms underlying depression and inflammation. Analysis of cytokines provides one promising approach for understanding the mechanisms that may contribute to MS symptoms. Methods: In this pilot study, we measured salivary levels of interleukin (IL)-6, IL-1beta (β), and IL-10 in 24 veterans with MS. Descriptive statistics were reported and Pearson correlation coefficients were obtained between cytokines and depression. Results: The anti-inflammatory cytokine IL-10 was significantly negatively associated with depression in veterans with MS (r = −0.47, p =.024). Conclusion: Cytokines may be useful for elucidating biological mechanisms associated with the depression and a measure for nurses caring for veterans with MS. © The Author(s) 2021.
Author Keywords
depression; inflammatory markers; multiple sclerosis; veterans
Funding details
University of WashingtonUW
Document Type: Article
Publication Stage: Article in Press
Source: Scopus