Neurosciences Commons^™

Novel Dominant And Recessive Variants In Human Robo1 Cause Distinct Neurodevelopmental Defects Through Different Mechanisms, Yan Huang, Mengqi Ma, Xiao Mao, Davut Pehlivan, Oguz Kanca, Feride Un-Candan, Li Shu, Gulsen Akay, Tadahiro Mitani, Shenzhao Lu, Sukru Candan, Hua Wang, Bo Xiao, James R Lupski, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

The Roundabout (Robo) receptors, located on growth cones of neurons, induce axon repulsion in response to the extracellular ligand Slit. The Robo family of proteins controls midline crossing of commissural neurons during development in flies. Mono- and bi-allelic variants in human ROBO1 (HGNC: 10249) have been associated with incomplete penetrance and variable expressivity for a breath of phenotypes, including neurodevelopmental defects such as strabismus, pituitary defects, intellectual impairment, as well as defects in heart and kidney. Here, we report two novel ROBO1 variants associated with very distinct phenotypes. A homozygous missense p.S1522L variant in three affected siblings with nystagmus; and …

Notes From An Epicenter: Navigating Behavioral Clinical Trials On Autism Spectrum Disorder Amid The Covid-19 Pandemic In The Bronx, Alaina S Berruti, Roseann C Schaaf, Emily A Jones, Elizabeth Ridgway, Rachel L. Dumont, Benjamin E Leiby, Catherine Sancimino, Misung Yi, Sophie Molholm

Department of Occupational Therapy Faculty Papers

Background: The COVID-19 pandemic impacted nearly all facets of our daily lives, and clinical research was no exception. Here, we discuss the impact of the pandemic on our ongoing, three-arm randomized controlled trial (RCT) Sensory Integration Therapy (SIT) in Autism: Mechanisms and Effectiveness (NCT02536365), which investigates the immediate and sustained utility of SIT to strengthen functional daily-living skills and minimize the presence of maladaptive sensory behaviors in autistic children.

Main text: In this text, we detail how we navigated the unique challenges that the pandemic brought forth between the years 2020 and 2021, including the need to rapidly …

Patients’ Attitudes Toward Deprescribing And Their Experiences Communicating With Clinicians And Pharmacists, Kaylee Marie Lukacena, James W. Keck, Patricia R. Freeman, Nancy Grant Harrington, Mark Huffmyer, Daniela C. Moga

Sanders-Brown Center on Aging Faculty Publications

Purpose: Developing effective deprescribing interventions relies on understanding attitudes, beliefs, and communication challenges of those involved in the deprescribing decision-making process, including the patient, the primary care clinician, and the pharmacist. The objective of this study was to assess patients’ beliefs and attitudes and identify facilitators of and barriers to deprescribing.

Methods: As part of a larger study, we recruited patients ⩾18years of age taking ⩾3 chronic medications. Participants were recruited from retail pharmacies associated with the University of Kentucky HealthCare system. They completed an electronic survey that included demographic information, questions about communication with their primary care clinician and …

Regulation Of Drosophila Oviduct Muscle Contractility By Octopamine, Sonali A Deshpande, Ethan W Rohrbach, James D Asuncion, Jenna Harrigan, Aditya Eamani, Ellery H Schlingmann, Daniel J Suto, Pei-Tseng Lee, Felix E Schweizer, Hugo J Bellen, David E Krantz

Duncan NRI Faculty and Staff Publications

Octopamine is essential for egg-laying in

Advancing The Assessment And Treatment Of Signs And Symptoms Of Parkinson Disease, David Scott May

WUSM Theses and Dissertations – All Programs

People with PD often report signs and symptoms that negatively impact quality of life. Among these are balance difficulties, impaired gait, and FOG. New treatment and assessment strategies for these signs and symptoms are needed, as current techniques are limited. While new treatment and assessment strategies continue to emerge, gaps in knowledge persist. Deep brain stimulation (DBS) has been utilized in many people with PD throughout the 21st century, but it is unknown specifically how subthalamic nucleus deep brain stimulation (STN-DBS) affects balance. Alternative treatment strategies, such as a dental mouthpiece, have also been proposed. While dental mouthpieces have shown …

Secure Human Action Recognition By Encrypted Neural Network Inference, Miran Kim, Xiaoqian Jiang, Kristin Lauter, Elkhan Ismayilzada, Shayan Shams

Faculty, Staff and Student Publications

Advanced computer vision technology can provide near real-time home monitoring to support "aging in place" by detecting falls and symptoms related to seizures and stroke. Affordable webcams, together with cloud computing services (to run machine learning algorithms), can potentially bring significant social benefits. However, it has not been deployed in practice because of privacy concerns. In this paper, we propose a strategy that uses homomorphic encryption to resolve this dilemma, which guarantees information confidentiality while retaining action detection. Our protocol for secure inference can distinguish falls from activities of daily living with 86.21% sensitivity and 99.14% specificity, with an average …

Improved Sars-Cov-2 Sequencing Surveillance Allows The Identification Of New Variants And Signatures In Infected Patients, Antonio Grimaldi, Francesco Panariello, Patrizia Annunziata, Teresa Giuliano, Michela Daniele, Biancamaria Pierri, Chiara Colantuono, Marcello Salvi, Valentina Bouché, Anna Manfredi, Maria Concetta Cuomo, Denise Di Concilio, Claudia Tiberio, Mariano Fiorenza, Giuseppe Portella, Ilaria Cimmino, Antonio Sorrentino, Giovanna Fusco, Maria Rosaria Granata, Pellegrino Cerino, Antonio Limone, Luigi Atripaldi, Andrea Ballabio, Davide Cacchiarelli

Duncan NRI Faculty and Staff Publications

Background: Genomic surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the only approach to rapidly monitor and tackle emerging variants of concern (VOC) of the COVID-19 pandemic. Such scrutiny is crucial to limit the spread of VOC that might escape the immune protection conferred by vaccination strategies or previous virus exposure. It is also becoming clear now that efficient genomic surveillance would require monitoring of the host gene expression to identify prognostic biomarkers of treatment efficacy and disease progression. Here we propose an integrative workflow to both generate thousands of SARS-CoV-2 genome sequences per week and analyze host …

Identification Of The Nrf2 Transcriptional Network As A Therapeutic Target For Trigeminal Neuropathic Pain, Chirag Vasavda, Risheng Xu, Jason Liew, Ruchita Kothari, Ryan S Dhindsa, Evan R Semenza, Bindu D Paul, Dustin P Green, Mark F Sabbagh, Joseph Y Shin, Wuyang Yang, Adele M Snowman, Lauren K Albacarys, Abhay Moghekar, Carlos A Pardo-Villamizar, Mark Luciano, Judy Huang, Chetan Bettegowda, Shawn G Kwatra, Xinzhong Dong, Michael Lim, Solomon H Snyder

Duncan NRI Faculty and Staff Publications

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the …

Characterization And Comparison Of Human Glioblastoma Models, Julia A. Schulz, Louis T. Rogers, Richard J. Kryscio, Anika M. S. Hartz, Björn Bauer

Sanders-Brown Center on Aging Faculty Publications

Abstract
Glioblastoma (GBM) is one of the deadliest cancers. Treatment options are limited, and median patient survival is only several months. Translation of new therapies is hindered by a lack of GBM models that fully recapitulate disease heterogeneity. Here, we characterize two human GBM models (U87-luc2, U251-RedFLuc). In vitro, both cell lines express similar levels of luciferase and show comparable sensitivity to temozolomide and lapatinib exposure. In vivo, however, the two GBM models recapitulate diferent aspects of the disease. U87-luc2 cells quickly grow into large, well-demarcated tumors; U251-RedFLuc cells form small, highly invasive tumors. Using a new method to assess …

Synergistic Neuroprotection By A Paf Antagonist Plus A Docosanoid In Experimental Ischemic Stroke: Dose-Response And Therapeutic Window, Madigan M. Reid, Andre Obenaus, Pranab K. Mukherjee, Larissa Khoutorova, Cassia R. Roque, Nicos A. Petasis, Reinaldo B. Oria, Ludmila Belayev, Nicolas G. Bazan

School of Graduate Studies Faculty Publications

Objective: We tested the hypothesis that blocking pro-inflammatory platelet-activating factor receptor (PAFR) with LAU-0901 (LAU) plus administering a selected docosanoid, aspirin-triggered neuroprotectin D1 (AT-NPD1), which activates cell-survival pathways after middle cerebral artery occlusion (MCAo), would lead to neurological recovery. Dose-response and therapeutic window were investigated. Materials and methods: Male SD rats were subjected to 2 hours of MCAo. Behavior testing (days 1-7) and ex vivo MRI on day 7 were conducted. In dose-response, rats were treated with LAU (45 and 60 mg/kg; IP), AT-NPD1 (111, 222, 333 µg/kg; IV), LAU+AT-NPD1 (LAU at 3 hours and AT-NPD1 at 3.15 hours) or …

Neuropsychology Of Primary Headache Disorders: A Meta-Analysis, Jasmin H. Pizer

Graduate Theses and Dissertations (2019 - present)

Objective: A meta-analysis was conducted comparing cognition on clinical measures between individuals with a primary headache disorder (PHD) and healthy controls (HC). Data Selection: The University of South Alabama Libraries’ OneSearch and PubMed, with a uniform search-strategy, were used to locate original research comparing cognition between PHD and HC samples. Analyses were modeled under random effects. Hedge’s g was used as a bias-corrected estimate of effect size. Between-study heterogeneity was assessed using Cochran’s Q and I2. Data Synthesis: The initial search interval spanned inception–May 2021 and yielded 6692 results. Fifty-seven studies were analyzed. Meta-analysis showed a significant combined effect size …

Vasopressin Resets The Central Circadian Clock In A Manner Influenced By Sex And Vasoactive Intestinal Polypeptide Signaling, Kayla E. Rohr, Thomas Inda, Jennifer A. Evans

Biomedical Sciences Faculty Research and Publications

Background/Aims: Circadian rhythms in behavior and physiology are programmed by the suprachiasmatic nucleus (SCN) of the hypothalamus. A subset of SCN neurons produce the neuropeptide arginine vasopressin (AVP), but it remains unclear whether AVP signaling influences the SCN clock directly.

Methods: Here, we test that AVP signaling acting through V1A and V1B receptors influences molecular rhythms in SCN neurons. V1 receptor agonists were applied ex vivo to PERIOD2::LUCIFERASE SCN slices, allowing for real-time monitoring of changes in molecular clock function.

Results: V1A/B agonists reset the phase of the SCN molecular clock in a time-dependent manner, with larger magnitude responses by …

Event-Related Phase Synchronization Propagates Rapidly Across Human Ventral Visual Cortex, Oscar Woolnough, Kiefer J Forseth, Patrick S Rollo, Zachary J Roccaforte, Nitin Tandon

Faculty, Staff and Student Publications

Visual inputs to early visual cortex integrate with semantic, linguistic and memory inputs in higher visual cortex, in a manner that is rapid and accurate, and enables complex computations such as face recognition and word reading. This implies the existence of fundamental organizational principles that enable such efficiency. To elaborate on this, we performed intracranial recordings in 82 individuals while they performed tasks of varying visual and cognitive complexity. We discovered that visual inputs induce highly organized posterior-to-anterior propagating patterns of phase modulation across the ventral occipitotemporal cortex. At individual electrodes there was a stereotyped temporal pattern of phase progression …

Insulin Resistance In Depression: A Large Meta-Analysis Of Metabolic Parameters And Variation, Brisa S Fernandes, Estela Salagre, Nitesh Enduru, Iria Grande, Eduard Vieta, Zhongming Zhao

Faculty, Staff and Student Publications

Increased insulin resistance is recognized in psychiatric disorders, such as schizophrenia and bipolar disorder, but its occurrence in depression is less clear. Our aims were to verify if insulin resistance is altered in depression, to test the metabolic subgroup hypothesis of depression and if there are changes with antidepressants. Inclusion criteria were studies including adult subjects with depression and either a control group or follow-up after treatment with antidepressants, and assessing fasting insulin or glucose levels or the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index. Seventy studies with 240,704 participants were included. Both insulin levels and the HOMA-IR index …

Elucidating The Role Of Cerebellar Synaptic Dysfunction In C9orf72-Als/Ftd - A Systematic Review And Meta-Analysis, Aleksandra Kaliszewska, Joseph Allison, Tarik-Tarkan Col, Christopher Shaw, Natalia Arias

Faculty, Staff and Student Publications

A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with synaptic dysfunction identified as an early pathological hallmark. Although TDP-43 pathology and overt neurodegeneration are largely absent from the cerebellum, the pathological hallmarks of RNA foci and dipeptide repeat protein (DPR) inclusions are most abundant. Here, we present a systematic literature search in the databases of PubMed, Scopus, Embase, Web of Science and Science Direct up until March 5, 2021, which yielded 19,515 publications. Following the exclusion criteria, 72 articles were included having referred to C9orf72 …

Investigating Conserved Mechanisms For Embryonic Eye Regrowth In Xenopus Laevis, Cindy Kha

UNLV Theses, Dissertations, Professional Papers, and Capstones

Regeneration is a complex process to replace or restore tissue after damage. However, animals vary in their ability to regenerate tissue, and humans are limited in their abilities. Understanding how regeneration occurs in highly regenerative vertebrates, such as in Xenopus laevis frogs will lead to defining common regeneration mechanisms. In recent years, eye regeneration research in Xenopus laevis tadpoles provided new promising insight into the mechanisms necessary for repair of damaged eye tissue. Much progress has been made towards understanding the regenerative capability of the complex eye since Xenopus tadpoles can regenerate mature eye tissues, including: the optic nerve, retina, …

Cognitive Testing For Sport Concussion: The Immediate Post-Concussion Assessment And Cognitive Testing (Impact), Julia E. Maietta

UNLV Theses, Dissertations, Professional Papers, and Capstones

Sport concussion is among the most common injuries for an athlete to experience during sport participation. Because of the complex pathophysiological process that affects the brain during and after concussion, symptoms can be heterogeneous in presence and severity. Although most acute symptoms (e.g., headache, slowed processing speed, loss of consciousness, irritability, depression, anxiety) resolve within seven to 10 days for most athletes, there is evidence that higher initial symptom burden and other genetically based differences can lead to longer symptom duration and complicated recovery post-concussion. Because structural changes that commonly occur as a result of concussion (e.g., diffuse axonal injury) …

Genome Sequencing In The Parkinson Disease Clinic, Emily J Hill, Laurie A Robak, Rami Al-Ouran, Jennifer Deger, Jamie C Fong, Paul Jerrod Vandeventer, Emily Schulman, Sindhu Rao, Hiba Saade, Joseph M Savitt, Rainer Von Coelln, Neeja Desai, Harshavardhan Doddapaneni, Sejal Salvi, Shannon Dugan-Perez, Donna M Muzny, Amy L Mcguire, Zhandong Liu, Richard A Gibbs, Chad Shaw, Joseph Jankovic, Lisa M Shulman, Joshua M Shulman

Duncan NRI Faculty and Staff Publications

Background and objectives: Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics.

Methods: In 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well …

Ankle2-Related Microcephaly: A Variable Microcephaly Syndrome Resembling Zika Infection, Ajay X Thomas, Nichole Link, Laurie A Robak, Gail Demmler-Harrison, Emily C Pao, Audrey E Squire, Savannah Michels, Julie S Cohen, Anne Comi, Paolo Prontera, Alberto Verrotti Di Pianella, Giuseppe Di Cara, Livia Garavelli, Stefano Giuseppe Caraffi, Carlo Fusco, Roberta Zuntini, Kendall C Parks, Elliott H Sherr, Mais O Hashem, Sateesh Maddirevula, Fowzan S Alkuraya, Isphana A F Contractar, Jennifer E Neil, Christopher A Walsh, Hugo J Bellen, Hsiao-Tuan Chao, Robin D Clark, Ghayda M Mirzaa

Duncan NRI Faculty and Staff Publications

Objective: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus.

Methods: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster.

Results: All individuals had MIC (z-score ≤ -3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, …

Sox9 Directs Divergent Epigenomic States In Brain Tumor Subtypes, Debosmita Sardar, Hsiao-Chi Chen, Amanda Reyes, Srinidhi Varadharajan, Antrix Jain, Carrie Mohila, Rachel Curry, Brittney Lozzi, Kavitha Rajendran, Alexis Cervantes, Kwanha Yu, Ali Jalali, Ganesh Rao, Stephen C Mack, Benjamin Deneen

Duncan NRI Faculty and Staff Publications

Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZR

Cardiovascular Adverse Events In Oncology Trials: Understanding And Appreciating The Differences Between Clinical Trial Data And Real-World Reports, Michael S Ewer, Jay Herson

Duncan NRI Faculty and Staff Publications

Reports of cardiac adverse events from oncology clinical trials often are at variance with reports derived from clinical observations or data-base reviews. These differences may lead to confusion, as different levels of risks abound in the literature, and the true cardiac risk of using some agents is uncertain. Additionally, such discrepancies may lead to the creation of over-cautious surveillance algorithms. Reasons for these reported differences are complex and often reflect subtleties in the criteria for individual patient evaluation. Both clinical trial data and real-world data have potential flaws that make reconciliation problematic. Importantly, however, both provide crucial information regarding the …

Editorial: Glia-Mediated Neurotoxicity: Uncovering The Molecular Mechanisms, Amit K Srivastava, Barbara Lukomska, Lorraine Iacovitti

Farber Institute for Neuroscience Faculty Papers

No abstract provided.

An Il1rl1 Genetic Variant Lowers Soluble St2 Levels And The Risk Effects Of Apoe-Ε4 In Female Patients With Alzheimer’S Disease, Yuanbing Jiang, Xiaopu Zhou, Hui Yi Wong, Li Ouyang, Fanny C. F. Ip, Vicky M. N. Chau, Shun-Fat Lau, Wei Wu, Daniel Y. K. Wong, Heukjin Seo, Wing-Yu Fu, Nicole C. H. Lai, Yuewen Chen, Alzheimer’S Disease Neuroimaging Initiative, Charles D. Smith, Gregory A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad

Sanders-Brown Center on Aging Faculty Publications

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD …

Brain-Wide Analysis Of The Supraspinal Connectome Reveals Anatomical Correlates To Functional Recovery After Spinal Injury, Zimei Wang, Adam Romanski, Vatsal Mehra, Yunfang Wang, Matthew Brannigan, Benjamin C. Campbell, Gregory A. Petsko, Pantelis Tsoulfas, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

The supraspinal connectome is essential for normal behavior and homeostasis and consists of numerous sensory, motor, and autonomic projections from brain to spinal cord. Study of supraspinal control and its restoration after damage has focused mostly on a handful of major populations that carry motor commands, with only limited consideration of dozens more that provide autonomic or crucial motor modulation. Here, we assemble an experimental workflow to rapidly profile the entire supraspinal mesoconnectome in adult mice and disseminate the output in a web-based resource. Optimized viral labeling, 3D imaging, and registration to a mouse digital neuroanatomical atlas assigned tens of …

Cryo-Em Structure Of The Human Kv3.1 Channel Reveals Gating Control By The Cytoplasmic T1 Domain, Gamma Chi, Qiansheng Liang, Akshay Sridhar, John B Cowgill, Kasim Sader, Mazdak Radjainia, Pu Qian, Pablo Castro-Hartmann, Shayla Venkaya, Nanki Kaur Singh, Gavin Mckinley, Alejandra Fernandez-Cid, Shubhashish M M Mukhopadhyay, Nicola A Burgess-Brown, Lucie Delemotte, Manuel Covarrubias, Katharina L Dürr

Department of Neuroscience Faculty Papers

Kv3 channels have distinctive gating kinetics tailored for rapid repolarization in fast-spiking neurons. Malfunction of this process due to genetic variants in the KCNC1 gene causes severe epileptic disorders, yet the structural determinants for the unusual gating properties remain elusive. Here, we present cryo-electron microscopy structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic tetramerization domain T1 which facilitates interactions with C-terminal axonal targeting motif and key components of the gating machinery. Additional interactions between S1/S2 linker and turret domain strengthen the interface between voltage sensor and pore domain. Supported by molecular dynamics simulations, electrophysiological and …

Neuronal Activity Induces Glucosylceramide That Is Secreted Via Exosomes For Lysosomal Degradation In Glia, Liping Wang, Guang Lin, Zhongyuan Zuo, Yarong Li, Seul Kee Byeon, Akhilesh Pandey, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Recessive variants in GBA1 cause Gaucher disease, a prevalent form of lysosome storage disease. GBA1 encodes a lysosomal enzyme that hydrolyzes glucosylceramide (GlcCer) into glucose and ceramide. Its loss causes lysosomal dysfunction and increased levels of GlcCer. We generated a null allele of the Drosophila ortholog Gba1b by inserting the Gal4 using CRISPR-Cas9. Here, we show that Gba1b is expressed in glia but not in neurons. Glial-specific knockdown recapitulates the defects found in Gba1b mutants, and these can be rescued by glial expression of human GBA1. We show that GlcCer is synthesized upon neuronal activity, and it is transported …

Biallelic Variants In Wars1 Cause A Highly Variable Neurodevelopmental Syndrome And Implicate A Critical Exon For Normal Auditory Function, Sheng Jia Lin, Barbara Vona, Hillary M. Porter, Mahmoud Izadi, Kevin Huang, Yves Lacassie, Jill A. Rosenfeld, Saadullah Khan, Cassidy Petree, Tayyiba A. Ali, Nazif Muhammad, Sher A. Khan, Noor Muhammad, Pengfei Liu, Marie Louise Haymon, Franz Rüschendorf, Il Keun Kong, Linda Schnapp, Natasha Shur, Lynn Chorich, Lawrence Layman, Thomas Haaf, Ehsan Pourkarimi, Hyung Goo Kim, Gaurav K. Varshney

School of Medicine Faculty Publications

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well …

Γ-Secretase Promotes Drosophila Postsynaptic Development Through The Cleavage Of A Wnt Receptor, Lucas J Restrepo, Alison T Depew, Elizabeth R Moese, Stephen R Tymanskyj, Michael J Parisi, Michael A Aimino, Juan Carlos Duhart, Hong Fei, Timothy J Mosca

Farber Institute for Neuroscience Faculty Papers

Developing synapses mature through the recruitment of specific proteins that stabilize presynaptic and postsynaptic structure and function. Wnt ligands signaling via Frizzled (Fz) receptors play many crucial roles in neuronal and synaptic development, but whether and how Wnt and Fz influence synaptic maturation is incompletely understood. Here, we show that Fz2 receptor cleavage via the γ-secretase complex is required for postsynaptic development and maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to recruit postsynaptic scaffolding and cytoskeletal proteins, leading to behavioral deficits. Introducing presenilin mutations linked to familial early-onset Alzheimer's disease into flies leads to synaptic maturation phenotypes …

A Spatiotemporal Map Of Reading Aloud, Oscar Woolnough, Cristian Donos, Aidan Curtis, Patrick S Rollo, Zachary J Roccaforte, Stanislas Dehaene, Simon Fischer-Baum, Nitin Tandon

Faculty, Staff and Student Publications

Reading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans (26 male, 20 female) as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband γ activity varies with multiple word attributes critical to reading speed: lexicality, word frequency, and orthographic neighborhood. We found that lexicality is encoded …

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.