Neurology Commons^™

Cd11bhigh B Cells Increase After Stroke And Regulate Microglia: Cd11bhigh B Cells Increase After Stroke And Regulate Mg, Janelle M Korf, Pedram Honarpisheh, Eric C Mohan, Anik Banerjee, Maria P Blasco-Conesa, Parisa Honarpisheh, Gary U Guzman, Romeesa Khan, Bhanu P Ganesh, Amy L Hazen, Juneyoung Lee, Aditya Kumar, Louise D Mccullough, Anjali Chauhan

Faculty, Staff and Student Publications

Recent studies have highlighted the deleterious contributions of B cells to post-stroke recovery and cognitive decline. Different B cell subsets have been proposed based on expression levels of transcription factors (e.g. T-bet) as well as specific surface proteins. CD11b (α-chain of integrin) is expressed by several immune cell types and is involved in regulation of cell motility, phagocytosis, and other essential functions of host immunity. Although B cells express CD11b, the CD11b^high subset of B cells has not been well characterized, especially in immune dysregulation seen with aging and after stroke. Here, we investigate the role of CD11b^{high …}

Renin-Angiotensin System In Huntington's Disease: Evidence From Animal Models And Human Patients, Lucas M Kangussu, Natalia P Rocha, Priscila A C Valadão, Thatiane C G Machado, Kívia B Soares, Julliane V Joviano-Santos, Leigh B Latham, Gabriela D Colpo, Ana Flávia Almeida-Santos, Erin Furr Stimming, Ana Cristina Simões E Silva, Antônio L Teixeira, Aline Silva Miranda, Cristina Guatimosim

Faculty, Staff and Student Publications

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside …

Small Rna Signatures Of Acute Ischemic Stroke In L1cam Positive Extracellular Vesicles, Michael A Lopez, Ying Si, Xianzhen Hu, Valentyna Williams, Fuad Qushair, Jackson Carlyle, Lyndsy Alesce, Michael Conklin, Shawn Gilbert, Marcas M Bamman, Matthew S Alexander, Peter H King

Faculty, Staff and Student Publications

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by skeletal muscle instability, progressive muscle wasting, and fibrosis. A major driver of DMD pathology stems from aberrant upregulation of transforming growth factor β (TGFβ) signaling. In this report, we investigated the major transducers of TGFβ signaling, i.e., receptor Smads (R-Smads), in DMD patient skeletal muscle and observed a 48-fold increase in Smad8 mRNA. Smad1, Smad2, Smad3, and Smad5 mRNA were only minimally increased. A similar pattern was observed in the muscle from the mdx5cv mouse. Western blot analysis showed upregulation of phosphorylated Smad1, Smad5, and Smad8 …

Gene-Based Therapeutics For Rare Genetic Neurodevelopmental Psychiatric Disorders, Beverly L Davidson, Guangping Gao, Elizabeth Berry-Kravis, Allison M Bradbury, Carsten Bönnemann, Joseph D Buxbaum, Gavin R Corcoran, Steven J Gray, Heather Gray-Edwards, Robin J Kleiman, Adam J Shaywitz, Dan Wang, Huda Y Zoghbi, Terence R Flotte, Sitra Tauscher-Wisniewski, Cynthia J Tifft, Mustafa Sahin

Duncan NRI Faculty and Staff Publications

We are in an emerging era of gene-based therapeutics with significant promise for rare genetic disorders. The potential is particularly significant for genetic central nervous system disorders that have begun to achieve Food and Drug Administration approval for select patient populations. This review summarizes the discussions and presentations of the National Institute of Mental Health-sponsored workshop "Gene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders," which was held in January 2021. Here, we distill the points raised regarding various precision medicine approaches related to neurodevelopmental and psychiatric disorders that may be amenable to gene-based therapies.

Transcription Factor Runx3 Mediates Plasticity Of Thgm Cells Toward Th1 Phenotype, Javad Rasouli, Giacomo Casella, Weifeng Zhang, Dan Xiao, Gaurav Kumar, Paolo Fortina, Guang-Xian Zhang, Bogoljub Ciric, Abdolmohamad Rostami

Department of Neurology Faculty Papers

GM-CSF-producing T helper (Th) cells play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Recent studies have identified a distinct population of GM-CSF-producing Th cells, named ThGM cells, that also express cytokines TNF, IL-2, and IL-3, but lack expression of master transcription factors (TF) and signature cytokines of commonly recognized Th cell lineages. ThGM cells are highly encephalitogenic in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Similar to Th17 cells, in response to IL-12, ThGM cells upregulate expression of T-bet and IFN-γ and switch their phenotype to Th1. Here we show that …

Chemotherapy Coupled To Macrophage Inhibition Induces T-Cell And B-Cell Infiltration And Durable Regression In Triple-Negative Breast Cancer, Swarnima Singh, Nigel Lee, Diego A Pedroza, Igor L Bado, Clark Hamor, Licheng Zhang, Sergio Aguirre, Jingyuan Hu, Yichao Shen, Yitian Xu, Yang Gao, Na Zhao, Shu-Hsia Chen, Ying-Wooi Wan, Zhandong Liu, Jeffrey T Chang, Daniel Hollern, Charles M Perou, Xiang H F Zhang, Jeffrey M Rosen

Duncan NRI Faculty and Staff Publications

Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful anti-tumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single cell RNA sequencing characterized tumor-infiltrating lymphocytes (TIL) including helper T cells and antigen-presenting …

A Peptide Blocking The Adora1-Neurabin Interaction Is Anticonvulsant And Inhibits Epilepsy In An Alzheimer's Model, Shalini Saggu, Yunjia Chen, Liping Chen, Diana Pizarro, Sandipan Pati, Wen Jing Law, Lori Mcmahon, Kai Jiao, Qin Wang

Faculty, Staff and Student Publications

Epileptic seizures are common sequelae of stroke, acute brain injury, and chronic neurodegenerative diseases, including Alzheimer's disease (AD), and cannot be effectively controlled in approximately 40% of patients, necessitating the development of novel therapeutic agents. Activation of the A1 receptor (A1R) by endogenous adenosine is an intrinsic mechanism to self-terminate seizures and protect neurons from excitotoxicity. However, targeting A1R for neurological disorders has been hindered by side effects associated with its broad expression outside the nervous system. Here we aim to target the neural-specific A1R/neurabin/regulator of G protein signaling 4 (A1R/neurabin/RGS4) complex that dictates A1R signaling strength and response outcome …

Co-Transmitting Neurons In The Lateral Septal Nucleus Exhibit Features Of Neurotransmitter Switching, Patrick J Hunt, Mikhail Kochukov, Brandon T Pekarek, Benjamin D W Belfort, Juan M Romero, Jessica L Swanson, Benjamin R Arenkiel

Faculty, Staff and Students Publications

The lateral septal nucleus (LSN) is a highly interconnected region of the central brain whose activity regulates widespread circuitry. As such, the mechanisms that govern neuronal activity within the LSN have far-reaching implications on numerous brain-wide nuclei, circuits, and behaviors. We found that GABAergic neurons within the LSN express markers that mediate the release of acetylcholine (ACh). Moreover, we show that these vGATLSN neurons release both GABA and ACh onto local glutamatergic LSN neurons. Using both short-term and long-term neuronal labeling techniques we observed expression of the cholinergic neuron marker Choline Acetyltransferase (ChAT) in vGATLSN neurons. These findings provide evidence …

Expression Of 4e-Bp1 In Juvenile Mice Alleviates Mtor-Induced Neuronal Dysfunction And Epilepsy, Lena H Nguyen, Youfen Xu, Travorn Mahadeo, Longbo Zhang, Tiffany V Lin, Heather A Born, Anne E Anderson, Angélique Bordey

Faculty, Staff and Students Publications

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational …

A Weakened Recurrent Circuit In The Hippocampus Of Rett Syndrome Mice Disrupts Long-Term Memory Representations, Lingjie He, Matthew S Caudill, Junzhan Jing, Wei Wang, Yaling Sun, Jianrong Tang, Xiaolong Jiang, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Successful recall of a contextual memory requires reactivating ensembles of hippocampal cells that were allocated during memory formation. Altering the ratio of excitation-to-inhibition (E/I) during memory retrieval can bias cell participation in an ensemble and hinder memory recall. In the case of Rett syndrome (RTT), a neurological disorder with severe learning and memory deficits, the E/I balance is altered, but the source of this imbalance is unknown. Using in vivo imaging during an associative memory task, we show that during long-term memory retrieval, RTT CA1 cells poorly distinguish mnemonic context and form larger ensembles than wild-type mouse cells. Simultaneous multiple …

Biliverdin Reductase Bridges Focal Adhesion Kinase To Src To Modulate Synaptic Signaling, Chirag Vasavda, Evan R Semenza, Jason Liew, Ruchita Kothari, Ryan S Dhindsa, Shruthi Shanmukha, Anthony Lin, Robert Tokhunts, Cristina Ricco, Adele M Snowman, Lauren Albacarys, Francesco Pastore, Cristian Ripoli, Claudio Grassi, Eugenio Barone, Michael D Kornberg, Xinzhong Dong, Bindu D Paul, Solomon H Snyder

Duncan NRI Faculty and Staff Publications

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity—the neuronal process of adapting to diverse and variable inputs—depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR-null (BVR−/−) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. …

Characterization Of Retinal Function And Structure In The Mptp Murine Model Of Parkinson's Diseasecharacterization Of Retinal Function And Structure In The Mptp Murine Model Of Parkinson’S Disease, Katie K N Tran, Vickie H Y Wong, Jeremiah K H Lim, Ali Shahandeh, Anh Hoang, David I Finkelstein, Bang V Bui, Christine T O Nguyen

Faculty, Staff and Student Publications

In addition to well characterized motor symptoms, visual disturbances are increasingly recognized as an early manifestation in Parkinson's disease (PD). A better understanding of the mechanisms underlying these changes would facilitate the development of vision tests which can be used as preclinical biomarkers to support the development of novel therapeutics for PD. This study aims to characterize the retinal phenotype of a mouse model of dopaminergic dysfunction and to examine whether these changes are reversible with levodopa treatment. We use a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to characterize the neurotoxic effects of MPTP on in vivo retinal function (electroretinography, …

Cross-Species Genetic Screens Identify Transglutaminase 5 As A Regulator Of Polyglutamine-Expanded Ataxin-1, Won-Seok Lee, Ismael Al-Ramahi, Hyun-Hwan Jeong, Youjin Jang, Tao Lin, Carolyn J Adamski, Laura A Lavery, Smruti Rath, Ronald Richman, Vitaliy V Bondar, Elizabeth Alcala, Jean-Pierre Revelli, Harry T Orr, Zhandong Liu, Juan Botas, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, …

Reduction Of Mutant Atxn1 Rescues Premature Death In A Conditional Sca1 Mouse Model, James P Orengo, Larissa Nitschke, Meike E Van Der Heijden, Nicholas A Ciaburri, Harry T Orr, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses, motor neurons are affected, and their dysfunction contributes toward the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1, we created a conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model; however, they took twice as long to develop. We found that …

Dynamics Of Huntingtin Protein Interactions In The Striatum Identifies Candidate Modifiers Of Huntington Disease, Todd M Greco, Christopher Secker, Eduardo Silva Ramos, Joel D Federspiel, Jeh-Ping Liu, Alma M Perez, Ismael Al-Ramahi, Jeffrey P Cantle, Jeffrey B Carroll, Juan Botas, Scott O Zeitlin, Erich E Wanker, Ileana M Cristea

Duncan NRI Faculty and Staff Publications

Huntington’s disease (HD) is a monogenic neurodegenerative disorder with one causative gene, huntingtin (HTT). Yet, HD pathobiology is multifactorial, suggesting that cellular factors influence disease progression. Here, we define HTT protein-protein interactions (PPIs) perturbed by the mutant protein with expanded polyglutamine in the mouse striatum, a brain region with selective HD vulnerability. Using metabolically labeled tissues and immunoaffinity purification-mass spectrometry, we establish that polyglutamine-dependent modulation of HTT PPI abundances and relative stability starts at an early stage of pathogenesis in a Q140 HD mouse model. We identify direct and indirect PPIs that are also genetic disease modifiers using in-cell two-hybrid …

Disrupting The Myc-Tfeb Circuit Impairs Amino Acid Homeostasis And Provokes Metabolic Anergy, Mario R Fernandez, Franz X Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K Schaub, Frank C Dorsey, Min Liu, Meredith A Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M Koomen, Anders E Berglund, John L Cleveland

Duncan NRI Faculty and Staff Publications

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA …

Daam2 Regulates Myelin Structure And The Oligodendrocyte Actin Cytoskeleton Through Rac1 And Gelsolin, Carlo D Cristobal, Chih-Yen Wang, Zhongyuan Zuo, Joshua A Smith, Aaron Lindeke-Myers, Hugo J Bellen, Hyun Kyoung Lee

Duncan NRI Faculty and Staff Publications

Myelin is essential to neuronal health and CNS function, and oligodendrocytes (OLs) undergo a complex process of cytoskeletal remodeling to form compact myelin sheaths. We previously discovered that a formin protein, Dishevelled associated activator of morphogenesis 2 (Daam2), suppresses OL differentiation through Wnt signaling; however, its role in cytoskeletal control remains unknown. To investigate this, we used OL-specific Daam2 conditional knockout (Daam2 cKO) mice of either sex and found myelin decompaction during an active period of myelination in postnatal development and motor coordination deficits in adulthood. Using primary OL cultures, we found Daam2-depleted OLs showed morphologic dysregulation during differentiation, suggesting …

Clinical Exome Sequencing Data Reveal High Diagnostic Yields For Congenital Diaphragmatic Hernia Plus (Cdh+) And New Phenotypic Expansions Involving Cdh, Tiana M Scott, Ian M Campbell, Andres Hernandez-Garcia, Seema R Lalani, Pengfei Liu, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.

Methods: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.

Results: Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other …

Disruption Of Mecp2-Tcf20 Complex Underlies Distinct Neurodevelopmental Disorders, Jian Zhou, Hamdan Hamdan, Hari Krishna Yalamanchili, Kaifang Pang, Amy E Pohodich, Joanna Lopez, Yingyao Shao, Juan A Oses-Prieto, Lifang Li, Wonho Kim, Mark A Durham, Sameer S Bajikar, Donna J Palmer, Philip Ng, Michelle L Thompson, E Martina Bebin, Amelie J Müller, Alma Kuechler, Antje Kampmeier, Tobias B Haack, Alma L Burlingame, Zhandong Liu, Matthew N Rasband, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

MeCP2 is associated with Rett syndrome (RTT), MECP2 duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused …

Impairment Of Autophagy After Spinal Cord Injury Potentiates Neuroinflammation And Motor Function Deficit In Mice, Yun Li, Zhuofan Lei, Rodney M Ritzel, Junyun He, Hui Li, Harry M C Choi, Marta M Lipinski, Junfang Wu

Faculty, Staff and Student Publications

Autophagy is a catabolic process that degrades cytoplasmic constituents and organelles in the lysosome, thus serving an important role in cellular homeostasis and protection against insults. We previously reported that defects in autophagy contribute to neuronal cell damage in traumatic spinal cord injury (SCI). Recent data from other inflammatory models implicate autophagy in regulation of immune and inflammatory responses, with low levels of autophagic flux associated with pro-inflammatory phenotypes. In the present study, we examined the effects of genetically or pharmacologically manipulating autophagy on posttraumatic neuroinflammation and motor function after SCI in mice.

Methods: Young adult male C57BL/6, CX3CR1-GFP, autophagy …

A T-Cell Engaging Bispecific Antibody With A Tumor-Selective Bivalent Folate Receptor Alpha Binding Arm For The Treatment Of Ovarian Cancer, Brian C Avanzino, Kirthana Prabhakar, Pranjali Dalvi, Sharon Hartstein, Hannes Kehm, Aarti Balasubramani, Andrew A Boudreau, Ben Buelow, Karen Chang, Laura M Davison, Suhasini Iyer, Vidyut Kalwit, Kristin Lewis Wilson, Harbani K Malik-Chaudhry, Will Pierson, Geovanni Pineda, Udaya S Rangaswamy, Sowmya Saiganesh, Ute Schellenberger, Harshad S Ugamraj, Rodolfovan D Yabut, Roland Buelow, Jocelyn Chapman, Nathan D Trinklein, Katherine E Harris

Faculty, Staff and Student Publications

The use of T-cell engagers (TCEs) to treat solid tumors is challenging, and several have been limited by narrow therapeutic windows due to substantial on-target, off-tumor toxicities due to the expression of low levels of target antigens on healthy tissues. Here, we describe TNB-928B, a fully human TCE that has a bivalent binding arm for folate receptor alpha (FRα) to selectively target FRα overexpressing tumor cells while avoiding the lysis of cells with low levels of FRα expression. The bivalent design of the FRα binding arm confers tumor selectivity due to low-affinity but high-avidity binding to high FRα antigen density …

Exogenous Inter-Α Inhibitor Proteins Prevent Cell Death And Improve Ischemic Stroke Outcomes In Mice, Louise D Mccullough, Meaghan Roy-O'Reilly, Yun-Ju Lai, Anthony Patrizz, Yan Xu, Juneyoung Lee, Aleah Holmes, Daniel C Kraushaar, Anjali Chauhan, Lauren H Sansing, Barbara S Stonestreet, Liang Zhu, Julia Kofler, Yow-Pin Lim, Venugopal Reddy Venna

Faculty, Staff and Students Publications

Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when …

Macrocyclic Immunoproteasome Inhibitors As A Potential Therapy For Alzheimer's Disease, Min Jae Lee, Deepak Bhattarai, Hyeryung Jang, Ahreum Baek, In Jun Yeo, Seongsoo Lee, Zachary Miller, Sukyeong Lee, Jin Tae Hong, Dong-Eun Kim, Wooin Lee, Kyung Bo Kim

Faculty, Staff and Students Publications

Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (

Deciphering An Agrp-Serotoninergic Neural Circuit In Distinct Control Of Energy Metabolism From Feeding, Yong Han, Guobin Xia, Dollada Srisai, Fantao Meng, Yanlin He, Yali Ran, Yang He, Monica Farias, Giang Hoang, István Tóth, Marcelo O Dietrich, Miao-Hsueh Chen, Yong Xu, Qi Wu

Children’s Nutrition Research Center Staff Publications

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons …

The Synergy Of Bet Inhibitors With Aurora A Kinase Inhibitors In Mycn-Amplified Neuroblastoma Is Heightened With Functional Tp53, Joanna S Yi, Oscar Sias-Garcia, Nicole Nasholm, Xiaoyu Hu, Amanda Balboni Iniguez, Matthew D Hall, Mindy Davis, Rajarshi Guha, Myrthala Moreno-Smith, Eveline Barbieri, Kevin Duong, Jessica Koach, Jun Qi, James E Bradner, Kimberly Stegmaier, William A Weiss, W Clay Gustafson

Faculty, Staff and Students Publications

Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We previously performed a viability screen of ∼1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Compared …

The Rac-Gef Tiam1 Promotes Dendrite And Synapse Stabilization Of Dentate Granule Cells And Restricts Hippocampal-Dependent Memory Functions, Jinxuan Cheng, Federico Scala, Francisco A Blanco, Sanyong Niu, Karen Firozi, Laura Keehan, Shalaka Mulherkar, Emmanouil Froudarakis, Lingyong Li, Joseph G Duman, Xiaolong Jiang, Kimberley F Tolias

Faculty, Staff and Students Publications

The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction is associated with neuropsychiatric disorders. Despite its importance, the molecular mechanisms regulating DG neural circuit assembly and function remain unclear. Here, we identify the Rac-GEF Tiam1 as an important regulator of DG development and associated memory processes. In the hippocampus, Tiam1 is predominantly expressed in the DG throughout life. Global deletion of Tiam1 in male mice results in DG granule cells with simplified dendritic arbors, reduced dendritic spine density, and diminished excitatory synaptic transmission. Notably, DG …

Ifn-Β Acts On Monocytes To Ameliorate Cns Autoimmunity By Inhibiting Proinflammatory Cross-Talk Between Monocytes And Th Cells., Javad Rasouli, Giacomo Casella, Larissa Ishikawa, Rodolfo Thome, Alexandra Boehm, Adam Ertel, Carolina R Melo-Silva, Elisabeth R. Mari, Patrizia Porazzi, Weifeng Zhang, Dan Xiao, Luis J. Sigal, Paolo Fortina, Guang-Xian Zhang, A M Rostami, Bogoljub Ciric

Department of Neurology Faculty Papers

IFN-β has been the treatment for multiple sclerosis (MS) for almost three decades, but understanding the mechanisms underlying its beneficial effects remains incomplete. We have shown that MS patients have increased numbers of GM-CSF+ Th cells in circulation, and that IFN-β therapy reduces their numbers. GM-CSF expression by myelin-specific Th cells is essential for the development of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These findings suggested that IFN-β therapy may function via suppression of GM-CSF production by Th cells. In the current study, we elucidated a feedback loop between monocytes and Th cells that amplifies autoimmune neuroinflammation, …

Social And Leisure Activities Predict Transitions In Cognitive Functioning In Older Mexican Adults: A Latent Transition Analysis Of The Mexican Health And Aging Study, Heather Mary Brown, Stephen A Murray, Hope Northrup, Kit Sing Au, Lee A Niswander

Faculty, Staff and Student Publications

Disruptions in neural tube (NT) closure result in neural tube defects (NTDs). To understand the molecular processes required for mammalian NT closure, we investigated the role of Snx3, a sorting nexin gene. Snx3−/− mutant mouse embryos display a fully-penetrant cranial NTD. In vivo, we observed decreased canonical WNT target gene expression in the cranial neural epithelium of the Snx3−/− embryos and a defect in convergent extension of the neural epithelium. Snx3−/− cells show decreased WNT secretion, and live cell imaging reveals aberrant recycling of the WNT ligand-binding protein WLS and mis-trafficking to the lysosome for degradation. The importance …

Nk Cell-Derived Gm-Csf Potentiates Inflammatory Arthritis And Is Negatively Regulated By Cis, Cynthia Louis, Fernando Souza-Fonseca-Guimaraes, Yuyan Yang, Damian D'Silva, Tobias Kratina, Laura Dagley, Soroor Hediyeh-Zadeh, Jai Rautela, Seth Lucian Masters, Melissa J Davis, Jeffrey J Babon, Bogoljub Ciric, Eric Vivier, Warren S Alexander, Nicholas D Huntington, Ian P Wicks

Department of Neurology Faculty Papers

Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18–dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also …

De Novo Frameshift Variants In The Neuronal Splicing Factor Nova2 Result In A Common C-Terminal Extension And Cause A Severe Form Of Neurodevelopmental Disorder, Francesca Mattioli, Gaelle Hayot, Nathalie Drouot, Bertrand Isidor, Jérémie Courraud, Maria-Victoria Hinckelmann, Frederic Tran Mau-Them, Chantal Sellier, Alica Goldman, Aida Telegrafi, Alicia Boughton, Candace Gamble, Sebastien Moutton, Angélique Quartier, Nolwenn Jean, Paul Van Ness, Sarah Grotto, Sophie Nambot, Ganka Douglas, Yue Cindy Si, Jamel Chelly, Zohra Shad, Elisabeth Kaplan, Richard Dineen, Christelle Golzio, Nicolas Charlet-Berguerand, Jean-Louis Mandel, Amélie Piton

Faculty, Staff and Students Publications

The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 …