Neurosciences Commons^™

Telethon Undiagnosed Disease Program: Structured Approach To Solving Rare Childhood-Onset Genetic Diseases, Annalaura Torella, Manuela Morleo, Carmine Spampanato, Raffaele Castello, Mariateresa Zanobio, Giulio Piluso, Pasquale Di Letto, Maria Elena Onore, Sarah Iffat Rahman, Francesco Musacchia, Michele Pinelli, Giuseppina Vitiello, Giulia De Riso, Angelo Selicorni, Milena Mariani, Cecilia Daolio, Valeria Capra, Marcello Scala, Francesca Nardecchia, Serena Galosi, Mario Mastrangelo, Filippo Manti, Donatella Milani, Corrado Romano, Donatella Greco, Claudia Ciaccio, Stefano D'Arrigo, Arianna De Laurentiis, Antonietta Coppola, Marcella Zollino, Domizia Pasquetti, Federica Francesca L'Erario, Albina Tummolo, Claudia Santoro, Livia Garavelli, Carla Marini, Stefania Bigoni, Alfonsina Tirozzi, Viviana Cetrangolo, Giancarlo Parenti, Diego Di Bernardo, Angela Peron, Silvia Maitz, Andrea Accogli, Gerarda Cappuccio, Sandro Banfi, Giorgio Casari, Andrea Ballabio, Nicola Brunetti-Pierri, Vincenzo Nigro, Telethon Undiagnosed Disease Study Group

Duncan NRI Faculty and Staff Publications

Purpose: Many children with severe genetic disorders remain undiagnosed despite advanced genomic technologies. Early diagnosis is vital for prognosis, genetic counseling, and targeted treatment development. This study aims to increase diagnostic rates in complex pediatric cases and foster research into disease mechanisms.

Methods: Launched in 2016, the Telethon Undiagnosed Diseases Program provides a structured, multicenter approach to rare disease diagnosis. Standardized case submission criteria ensured consistent clinical data collection. Children with severe, multisystemic disorders and prior negative genetic tests were eligible. After case approval, trio-based exome sequencing was performed, with regular reanalysis for unsolved cases until December 2024.

Results: Between …

35 Individuals With Huwe1-Related Neurodevelopmental Disorder And Suggested Clinical Evaluations, Mindy H. Li, Deziree L. Coleman, Kelsey Hogan, Danielle Luz, Lindsay Bhandari, Newell Belnap, Tiffany Busa, Charles Coutton, Klaus Dieterich, Svetlana Gorokhova, Clara Hildebrandt, Rachel Logan, Milena Mariani, Manuela Morleo, Vincenzo Nigro, John Pappas, Rachel Rabin, Kelly Schoch, Angelo Selicorni, Vandana Shashi, Rebecca Spillman, Jennifer Sullivan, Charlotte Tardy, Samantha A. Schrier Vergano, Brock Grill, Kristin Baranano

Department of Pediatrics Faculty Publications

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well …

Loss Of The Maternal Effect Gene Nlrp2 Impairs Embryonic And Extra-Embryonic Development, Revealing A Novel Genetic Cause Of Congenital Anomalies†, Momal Sharif, Zahra Anvar, Imen Chakchouk, Sara H El-Dessouky, Roni Zemet, Eric C Kao, Wessam E Sharaf-Eldin, Ying-Wooi Wan, Zhandong Liu, Pengfei Liu, Michael Jochum, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Maternal-effect genes (MEGs) play a crucial role in early mammalian development, and their dysfunction can lead to severe embryonic and extra-embryonic abnormalities. NLRP2, a MEG that encodes a subcortical maternal complex (SCMC) protein, has been implicated in preimplantation development, but its role after implantation remains underexplored. In this study, we investigated the developmental consequences of maternal Nlrp2 loss-of-function in a maternal knockout (KO) mouse model at embryonic day 11.5. Embryos derived from Nlrp2-KO females have abnormal yolk sac vasculature, increased embryonic resorption, craniofacial abnormalities, neural tube defects, and congenital heart defects. Placental architecture is disrupted with an altered junctional zone …

Exploring The Role Of Astrocyte System Xc– In Excitatory/Inhibitory Balance, Samantha Olivia Sutton

Theses - ALL

Astrocytes play a central role in maintaining excitatory/inhibitory (E/I) balance in the central nervous system by supporting intracellular glutathione (GSH) synthesis and regulating extracellular glutamate. System xc– (Sxc–), an obligate cystine/glutamate antiporter encoded by SLC7a11, couples the import of L-cystine with the export of L-glutamate. It is highly expressed throughout the cortex, hippocampus, striatum, and cerebellum, where its activity provides cystine—the rate-limiting substrate for cysteine-dependent GSH production—and contributes to ambient glutamatergic tone. Although global loss of Sxc– alters seizure threshold and redox homeostasis, whether these effects arise specifically from the loss of astrocytic Sxc– has remained unresolved. This thesis examined …

Discovery Of Small Molecules And A Druggable Groove That Regulate Dna Binding And Release Of The Ap-1 Transcription Factor Δfosb, Sean Mcneme, Yun Young Yim, Ashwani Kumar, Yi Li, Brandon Hughes, Corey Peyton St Romain, Galina Aglyamova, Jianping Chen, Nghi D Nguyen, Shanghua Fan, Gabriel S Stephens, Wen-Ning Zhao, Samantha Kruzshak, Molly Estill, Corrine Brener, Solange Tofani, Anil Kumar, Earnest P Chen, Nadeen Takatka, Alfred J Robison, Haiying Chen, Reid T Powell, Stephen J Haggarty, Clifford Stephan, Eric J Nestler, Jeannie Chin, Mischa Machius, Jia Zhou, Gabby Rudenko

Faculty, Staff and Students Publications

ΔFOSB, a member of the AP-1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel site on ΔFOSB, located outside the DNA-binding cleft, that accommodates small molecules. We show that sulfonic acid-containing compounds bind to this site via an induced-fit mechanism, reorienting side chains critical for DNA binding, and that they may hinder the ΔFOSB bZIP α-helix from binding to the major groove of DNA. In vivo, direct …

Abnormalities In Sensorimotor Brain Function Are Related To Chronicity Of Low Back Pain, Jo Armour Smith, Rongwen Tain, Kelli G. Sharp, Laura M. Glynn, Linda R. Van Dillen, Jesse V. Jacobs, Steven C. Cramer

Physical Therapy Faculty Articles and Research

Maladaptive plasticity in the brain may contribute to chronic low back pain (LBP) and underlie the altered postural control of the lumbopelvic musculature that is evident in some individuals with LBP. We recently described an MRI-compatible leg-raise paradigm to measure brain activity associated with lumbopelvic postural control. The objective of this study was to compare brain function in young adults with and without a history of LBP and to determine relationships between brain function, pain, and postural control characteristics. We recruited 55 participants with a history of LBP, who were asymptomatic when studied, and 30 healthy controls. Postural control during …

Metabolomic Profiling Reveals Brain Lipid Alterations In Pex7-Deficient Models Of Rhizomelic Chondrodysplasia Punctata, Riya Sankhe, Meredith I Williams, Wedad Fallatah, Laura Mackay, Mary Layne Brown, Pranjali Bhagwat, Sarah H Elsea, Nancy Braverman, Michael F Wangler

Duncan NRI Faculty and Staff Publications

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound …

Acute And Chronic Effects Of Neuroinflammation On Hippocampus And Anterior Cingulate Cortex Network Dynamics, Lauren A. Crew

UNLV Theses, Dissertations, Professional Papers, and Capstones

Neuroinflammation has emerged as a critical modulator of cognitive function and neural circuit dynamics, yet the distinct contributions of acute and chronic neuroinflammation to brain function remain poorly defined. This dissertation examines how inflammation independently alters large-scale neural activity and behavior, focusing on interactions between the hippocampus (HPC) and anterior cingulate cortex (ACC), regions essential for memory and executive processes. Using in vivo electrophysiological techniques in a rodent model, this study compares the effects of short-term (acute) and prolonged (chronic) neuroinflammatory states, induced via Poly I:C, on neural oscillations, regional coherence, and spatial coding. Findings reveal that even transient inflammation …

Seizures In Camp Settings, Sandra Shapiro, Taylor Gilman, Tamar Sternfield, Jolie Skivington

CompassPoint

Managing seizures in the summer camp environment presents unique challenges, requiring not only medical attention but also empathy and understanding from both peers and caregivers. Approximately 0.5–5% of children and adolescents will experience at least one afebrile seizure by adolescence and there is a 3.6% risk of experiencing at least one seizure in an 80-year-lifespan (Murphy et al., 1995 as cited in Wilfong, 2025). Recognizing how to support a child with seizures during the camp season is essential to promoting their safety and well-being while also ensuring they have a positive and inclusive camp experience.

Spike Timing Depended Plasticity Produces Unsupervised Learning Of Synergistic Muscle Feedback In A Synthetical Neural Network, Mark Allen Pupkiewicz

Dissertations and Theses

This study investigates how type Ia feedback from muscle spindles can be organized into groups representing agonistic muscle pairs through Spike Timing Dependent Plasticity (STDP). A single degree of freedom joint is actuated with four biologically modeled muscles forming two agonistic pairs. In order to emulate the sensory dynamics of biological muscle spindles, sensors in the model record the active length and velocity states of each muscle, the two primary factors eliciting type Ia afferent responses. In biological networks, synapses from Ia sensory neurons frequently activate interneurons representing agonistic muscle sources. This research investigates whether this organization can emerge in …

Functional Vs Anatomical Cortico-Striatal Connectivity In The Macaque Brain, Wei Tang, Megan E Monko, Zoe Liu, Ana M G Manea, Fernando A Ortega, Damyan Hart, Jason Zhou, Jan Zimmermann, Sarah R Heilbronner

Faculty, Staff and Students Publications

The cerebral cortex provides the main input to the striatum, constituting the first step in cortico-basal ganglia loops. Decades of careful anatomical tract-tracing research have established the exquisite topography of each cortical region's projection to the striatum in nonhuman primates. In parallel, neuroimaging research has demonstrated the relationship between cortico-striatal resting-state functional connectivity and specific cognitive, behavioral, psychiatric, and neurological states in humans. However, still unclear is the extent to which functional connectivity recapitulates the specific topographies of cortico-striatal anatomical connectivity. Here, we combined datasets of cortico-striatal anatomical and functional connectivity in macaques to determine the degree of overlap between …

Protein-Protein Interaction–Interfering Peptide Rescues Dysregulated Nmda Receptor Signaling, Robert E. Featherstone, Hongbin Li, Ameet S. Sengar, Karin E. Borgmann-Winter, Olya Melnychenko, Lindsey M. Crown, Ray L. Gifford, Felix Amirfathi, Anamika Banerjee, Aivi Tran, Krishna Parekh, Margaret Heller, Wenyu Zhang, Robert J. Gallop, Adam D. Marc, Pragya Komal, Michael W. Salter, Steven J. Siegel, Chang-Gyu Hahn

Farber Institute for Neuroscience Faculty Papers

The complex and heterogeneous genetic architecture of neuropsychiatric illnesses compels us to look beyond individual risk genes for therapeutic strategies and target the interactive dynamics and convergence of their protein products. A mechanistic substrate for convergence of synaptic neuropsychiatric risk genes are protein-protein interactions (PPIs) in the N-methyl-D-aspartate receptor (NMDAR) complex. NMDAR hypofunction in schizophrenia is associated with hypoactivity of Src kinase, resulting from convergent alterations in PPIs of Src with its partners. Of these, the association of Src with PSD-95, which inhibits the activity of this kinase in the NMDAR complex, is known to be increased in schizophrenia. Here, …

Super-Fast, Super-Early: High-Frequency Oscillations May Be A Prelude To Alzheimer's Dementia In Down Syndrome, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. Methods: Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10–20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. Results: Fourteen individuals with DS and five age-matched euploid …

Dopaminergic Regulation Of Aversive Motivation, Elaine M. Grafelman

Dissertations (1934 -)

We all experience adversity in our lives, and we must be able to effectively respond to these challenges in order to thrive. One way to respond to stressors is to change one’s behavior to cope with the stress. This can include escaping or avoiding the stressor, focusing effort to diminish the effect of the stressor, or other coping strategies such as drug use. In fact, stress is one of the principal triggers of relapse for those in the abstinence phase of a substance use disorder and it exacerbates a variety of other disorders. Therefore, it is critical to understand the …

Restoration Of Sfrp3 Preserves The Neural Stem Cell Pool And Spatial Discrimination Ability In A Mouse Model Of Alzheimer's Disease, Chia-Hsuan Fu, Jin Park, Umberto Tosi, Francisco A Blanco, Manuel Silva-Pérez, Kavitha Muralidharan, Jason C You, Minjung Lee, Gabriel S Stephens, Xiaohong Zhang, Yi Zheng, Helen Scharfman, Kimberley F Tolias, Jeannie Chin

Faculty, Staff and Students Publications

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of …

A Distinct Pp2a Subunit Regulates Local Protein Phosphorylation At The Axon Initial Segment, Andrew P Anderson, Sanghyun Kim, Allison J Melton, Xiaoyun Ding, Wei Zhang, Alexander B Saltzman, Anna Malovannaya, Matthew N Rasband, Yudong Gao

Faculty, Staff and Students Publications

Protein phosphorylation plays a crucial role in regulating the cytoskeletal and membrane proteins at the axon initial segment (AIS). However, our knowledge of AIS-specific kinases and phosphatases is very limited. Here, we report the identification of a protein phosphatase 2A (PP2A) B55 regulatory subunit enriched at the AIS in mice: Ppp2r2c. Our results demonstrate that PP2A-B55 subunits exhibit substantial heterogeneity in their subcellular localization and function. Notably, the Ppp2r2c subunit is selectively concentrated at the AIS, and this enrichment is driven by its unique structure. Utilizing a microelectrode array system (MEA), we show that Ppp2r2c modulates neuronal activity during in …

The Perspectives And Experiences Of Prospective Parents Declining Diagnostic Prenatal Genome Sequencing In Continuing Pregnancies With Fetal Structural Anomalies, Lisa S Weingarten, Allison Rosenbaum, Jessica De Voest, Stephanie Galloway, Jessica L Giordano, Samantha Stover, Lauren E Westerfield, Grant Bonesteele, Kelly L Gilmore, Leandra Tolusso, Beatrix Wong, A Theresa Wittman, Daniel T Swarr, Nancy Leslie, Anthony Johnson, Ignatia B Van Den Veyver, Neeta L Vora, Rebecca G Clifton, Aaron B Caughey, Ronald J Wapner, Wendy K Chung

Duncan NRI Faculty and Staff Publications

Objective: This study evaluates an understudied perspective: the experiences of prospective parents who decline prenatal genome sequencing (pGS) for continuing pregnancies with fetal structural anomalies.

Method: We recruited a total cohort of 300 parents of 150 pregnancies who declined pGS, including 33 individuals who underwent an invasive procedure. These parents were invited to participate in a semi-structured interview between 1 and 15 months post-partum. We used Thematic Analysis to code and analyze interviews.

Results: We interviewed 22 parents of 16 pregnancies. Reasons for declining testing included risks of invasive procedures (n = 19, 86%), lack of prenatally actionable findings (n …

Activation Of Pro-Regenerative Gene Programs In The Mature Central Nervous System, Elizabeth Carlisle Batsel

Dissertations (1934 -)

Spinal cord injury (SCI) affects millions of people worldwide. Damage to the spinal cord disrupts the long-distance axon tracts of central nervous system (CNS) neurons. These axons fail to regenerate, leading to permanent dysfunction. Past work has shown that CNS neurons lose the capacity to elongate their axons as they mature. Conversely, after injury, embryonic and peripheral nervous system (PNS) neurons can elongate axons towards target cells, driven by the growth cone at the growing tip of the axon. Previous research has identified transcription factor (TF) families, such as the SoxC family, that contribute to embryonic and peripheral neurons’ high …

Targeting Tet3 Suppresses Group 3 Medulloblastoma Stemness And Progression Via Impairing Hypomethylation Of Otx2 Super-Enhancer, Xuan Chen, Ziwei Wang, Yan Song, Yu Su, Yahui Zhao, Jiankang Li, Wei Wang, Jiao Zhang, Craig Daniels, Xiaochong Wu, Olivier Saulnier, Yanan Wang, Fei Liu, Kaiwen Deng, Dongming Han, Zijia Liu, Meiyu Li, Liam D Hendrikse, Alexandra Rasnitsyn, Evan Y Wang, Dongyang Wang, Zhaoyang Feng, Yanong Li, Zitong Zhao, Hongyu Yuan, Youliang Sun, Yifei Jiang, Yanfeng Shi, Tao Yang, Xueling Qi, Yong Hou, Chunde Li, Yong-Qiang Liu, Yu Tian, Shuaicheng Li, Xiaoguang Qiu, Michael D Taylor, Guo Liang Li, Tao Jiang, Hailong Liu

Faculty, Staff and Students Publications

Medulloblastoma (MB), particularly Group_3 (G3-MB), remains the most aggressive subgroup due to strong stemness and therapeutic resistance. Through genome-wide DNA methylation and transcriptomic analysis of human MB samples, we identify enhancer hypomethylation as a key feature sustaining G3-MB stemness and tumor progression. Notably, hypomethylation of the Otx2 super-enhancer (SE) is a prognostic marker and potential therapeutic target for G3-MB patients. We demonstrate that disrupting Otx2 SE activity effectively reduces tumor growth in vivo, highlighting its critical role in G3-MB maintenance. TET3, recruited by OTX2, demethylates the Otx2 SE, promoting chromatin opening and sustaining tumor proliferation and stemness. To translate these …

How Patients With Amyotrophic Lateral Sclerosis Perceive Respiratory Interventions: A Mixed-Methods Study To Inform Implementation Efforts, Jason Ackrivo, Danny Bracy, Lauren B. Elman, John Hansen-Flaschen, Zachary Simmons, Piera Pasinelli, Terry Heiman-Patterson, Steven M. Kawut, Meghan B. Lane-Fall

Department of Neuroscience Faculty Papers

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that commonly leads to respiratory failure. Early respiratory interventions that may improve symptoms and outcomes are underused when prescribed. We sought to characterize patient perspectives and preferences for respiratory care to enable identification of implementation strategies to improve the uptake of ALS respiratory interventions.

METHODS: A prospective multicenter mixed-methods observational study was conducted using semistructured interviews of participants recently diagnosed with ALS at 4 academic centers in the United States. Eligible patients were those with an ALS diagnosis in the previous 12 months, forced vital capacity < 80% predicted normal, or presence of dyspnea or orthopnea.

RESULTS: Twenty-four patients …