Hope Center member publications

Tracking plasticity of individual human brains
(2021) Current Opinion in Behavioral Sciences, 40, pp. 161-168. 

Newbold, D.J.^a , Dosenbach, N.U.^{a b c d e}

^a Department of Neurology – Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Radiology – Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Pediatrics – Washington University School of Medicine, St. Louis, MO 63110, United States
^d Program in Occupational Therapy – Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Biomedical Engineering – Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Understanding how behavior affects human brain organization was the original motivation behind Precision Functional Mapping (PFM), a deep phenotyping approach to human neuroimaging. Here we review the original PFM studies, as well as research investigating the impact of sensory and/or motor deprivation, or disuse, on brain function. Next, we discuss precision functional mapping of brain plasticity, focusing on experiments that tracked casting of the dominant upper extremity with daily resting-state functional MRI scans. Mechanisms that shape brain circuits during early development may persist into adulthood, helping to maintain the organization of disused circuits. © 2021

Funding details
14-011
MH121276, MH122066, MH124567, MH96773, NS088590, NS110332
Child Neurology FoundationCNF
McDonnell Center for Systems Neuroscience
Hope Center for Neurological Disorders
Jacobs Foundation2016121703

Document Type: Review
Publication Stage: Final
Source: Scopus

Epigenetic regulation during human cortical development: Seq-ing answers from the brain to the organoid
(2021) Neurochemistry International, 147, art. no. 105039, . 

Lewis, E.M.A., Kaushik, K., Sandoval, L.A., Antony, I., Dietmann, S., Kroll, K.L.

Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Avenue St, Louis, MO 63110, United States

Abstract
Epigenetic regulation plays an important role in controlling gene expression during complex processes, such as development of the human brain. Mutations in genes encoding chromatin modifying proteins and in the non-protein coding sequences of the genome can potentially alter transcription factor binding or chromatin accessibility. Such mutations can frequently cause neurodevelopmental disorders, therefore understanding how epigenetic regulation shapes brain development is of particular interest. While epigenetic regulation of neural development has been extensively studied in murine models, significant species-specific differences in both the genome sequence and in brain development necessitate human models. However, access to human fetal material is limited and these tissues cannot be grown or experimentally manipulated ex vivo. Therefore, models that recapitulate particular aspects of human fetal brain development, such as the in vitro differentiation of human pluripotent stem cells (hPSCs), are instrumental for studying the epigenetic regulation of human neural development. Here, we examine recent studies that have defined changes in the epigenomic landscape during fetal brain development. We compare these studies with analogous data derived by in vitro differentiation of hPSCs into specific neuronal cell types or as three-dimensional cerebral organoids. Such comparisons can be informative regarding which aspects of fetal brain development are faithfully recapitulated by in vitro differentiation models and provide a foundation for using experimentally tractable in vitro models of human brain development to study neural gene regulation and the basis of its disruption to cause neurodevelopmental disorders. © 2021 The Author(s)

Author Keywords
Chromatin;  Epigenetic regulation;  Human brain development;  Neuron;  Organoid;  Pluripotent stem cells

Funding details
National Institutes of HealthNIHR01MH124808, R01NS114551, T32 GM 7067, T32 GM 7067–43, U01 HG007530, U54 HD087011-S1
Institute of Clinical and Translational SciencesICTS
Children’s Discovery InstituteCDI
Colorado Clinical and Translational Sciences InstituteCCTSI
Centre de Recherches MathématiquesCRM
Center of Regenerative Medicine, Washington University in St. LouisCRM, WUSTL

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetic and heritable considerations in patients or families with both intracranial and extracranial aneurysms
(2021) Journal of Neurosurgery, 134 (6), pp. 1999-2006. 

Huguenard, A.L.^a , Gupta, V.P.^a , Braverman, A.C.^b , Dacey, R.G.^a

^a Department of Neurosurgery, Washington University, St. Louis, United States
^b Cardiovascular Division, Department of Medicine, Washington University, St. Louis, MO, United States

Document Type: Review
Publication Stage: Final
Source: Scopus

MiR-124 synergism with ELAVL3 enhances target gene expression to promote neuronal maturity
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (22), art. no. e2015454118, . 

Lu, Y.-L.^a b c , Liu, Y.^a b , McCoy, M.J.^a b d e , Yoo, A.S.^a b

^a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Program in Developmental, Regenerative and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States

Abstract
Neuron-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), direct cell fate switching of human fibroblasts to neurons when ectopically expressed by repressing antineurogenic genes. How these miRNAs function after the repression of fibroblast genes for neuronal fate remains unclear. Here, we identified targets of miR-9/9*-124 as reprogramming cells activate the neuronal program and reveal the role of miR-124 that directly promotes the expression of its target genes associated with neuronal development and function. The mode of miR-124 as a positive regulator is determined by the binding of both AGO and a neuron-enriched RNA-binding protein, ELAVL3, to target transcripts. Although existing literature indicates that miRNA–ELAVL family protein interaction can result in either target gene up-regulation or down-regulation in a context-dependent manner, we specifically identified neuronal ELAVL3 as the driver for miR-124 target gene up-regulation in neurons. In primary human neurons, repressing miR-124 and ELAVL3 led to the down-regulation of genes involved in neuronal function and process outgrowth and cellular phenotypes of reduced inward currents and neurite outgrowth. Our results highlight the synergistic role between miR-124 and RNA-binding proteins to promote target gene regulation and neuronal function. © 2021 National Academy of Sciences. All rights reserved.

Author Keywords
Direct reprogramming;  MicroRNA target;  MiR-124;  Neuronal maturity;  RNA-binding protein

Funding details
National Institutes of HealthNIHDP2NS083372, R01NS107488, RF1AG056296
University of WashingtonUWT32GM081739

Document Type: Article
Publication Stage: Final
Source: Scopus

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease
(2021) Human Molecular Genetics, 30 (9), pp. 811-822. 

Qin, W.^a , Zhou, A.^a , Zuo, X.^a , Jia, L.^a , Li, F.^a , Wang, Q.^a , Li, Y.^a , Wei, Y.^a , Jin, H.^a , Cruchaga, C.^b c d , Benitez, B.A.^b c , Jia, J.^a e f g

^a Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric DiseasesBeijing 100053, China
^b Department of Psychiatry, Washington University, St. Louis, MO 63110, USA
^c NeuroGenomics and Informatics Center, Washington University, St. Louis, MO 63110, USA
^d Department of Genetics, Washington University, St. Louis, MO 63110, USA
^e Beijing Key Laboratory of Geriatric Cognitive Disorders, Capital Medical UniversityBeijing 10053, China
^f Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical UniversityBeijing 10053, China
^g Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical UniversityBeijing 10053, China

Abstract
To identify novel risk genes and better understand the molecular pathway underlying Alzheimer’s disease (AD), whole-exome sequencing was performed in 215 early-onset AD (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Document Type: Article
Publication Stage: Final
Source: Scopus

A Rapid Motor Task-Based Screening Tool for Parkinsonism in Community-Based Studies
(2021) Frontiers in Neurology, 12, art. no. 653066, . 

Dlamini, W.W.^a , Nielsen, S.^a , Ushe, M.^a , Nelson, G.^b c , Racette, B.A.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Parktown, Johannesburg, South Africa
^c Institute for Global Health, University College London, London, United Kingdom

Abstract
Background: The prevalence of parkinsonism in developing countries is largely unknown due to difficulty in ascertainment because access to neurologists is often limited. Objective: Develop and validate a parkinsonism screening tool using objective motor task-based tests that can be administered by non-clinicians. Methods: In a cross-sectional population-based sample from South Africa, we evaluated 315 adults, age >40, from an Mn-exposed (smelter) community, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3), Purdue grooved pegboard, and kinematic-UPDRS3-based motor tasks. In 275 participants (training dataset), we constructed a linear regression model to predict UPDRS3. We selected motor task summary measures independently associated with UPDRS3 (p < 0.05). We validated the model internally in the remaining 40 participants from the manganese-exposed community (test dataset) using the area under the receiver operating characteristic curve (AUC), and externally in another population-based sample of 90 participants from another South African community with only background levels of environmental Mn exposure. Results: The mean UPDRS3 score in participants from the Mn-exposed community was 9.1 in both the training and test datasets (standard deviation = 6.4 and 6.1, respectively). Together, 57 (18.1%) participants in this community had a UPDRS3 ≥ 15, including three with Parkinson’s disease. In the non-exposed community, the mean UPDRS3 was 3.9 (standard deviation = 4.3). Three (3.3%) had a UPDRS3 ≥ 15. Grooved pegboard time and mean velocity for hand rotation and finger tapping tasks were strongly associated with UPDRS3. Using these motor task summary measures and age, the UPDRS3 predictive model performed very well. In the test dataset, AUCs were 0.81 (95% CI 0.68, 0.94) and 0.91 (95% CI 0.81, 1.00) for cut points for neurologist-assessed UPDRS3 ≥ 10 and UPDRS3 ≥ 15, respectively. In the external validation dataset, the AUC was 0.85 (95% CI 0.73, 0.97) for UPDRS3 ≥ 10. AUCs were 0.76–0.82 when excluding age. Conclusion: A predictive model based on a series of objective motor tasks performs very well in assessing severity of parkinsonism in both Mn-exposed and non-exposed population-based cohorts. © Copyright © 2021 Dlamini, Nielsen, Ushe, Nelson and Racette.

Author Keywords
kinematics;  manganese;  parkinsonism;  predictive model;  receiver operating characteristic

Funding details
K01ES028295, R01ES025991, R01ES026891-S1

Document Type: Article
Publication Stage: Final
Source: Scopus

Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain
(2021) Protein Science, . 

Ryan, J.J., Bao, A., Bell, B., Ling, C., Jackrel, M.E.

Department of Chemistry, Washington University, St. Louis, MO, United States

Abstract
Hsp104, a yeast protein disaggregase, can be potentiated via numerous missense mutations at disparate locations throughout the coiled-coil middle domain (MD). Potentiated Hsp104 variants can counter the toxicity and misfolding of TDP-43, FUS, and α-synuclein, proteins which are implicated in neurodegenerative disorders. However, potentiated MD variants typically exhibit off-target toxicity. Further, it has remained confounding how numerous degenerate mutations confer potentiation, hampering engineering of therapeutic Hsp104 variants. Here, we sought to comprehensively define the key drivers of Hsp104 potentiation. Using scanning mutagenesis, we iteratively studied the effects of modulation at each position in the Hsp104 MD. Screening this library to identify enhanced variants reveals that missense mutations at 26% of positions in the MD yield variants that counter FUS toxicity. Modulation of the helix 2–helix 3/4 MD interface potentiates Hsp104, whereas mutations in the analogous helix 1–2 interface do not. Surprisingly, we find that there is a higher likelihood of enhancing Hsp104 activity against human disease substrates than impairing Hsp104 native function. We find that single mutations can broadly destabilize the MD structure and lead to functional potentiation, suggesting this may be a common mechanism conferring Hsp104 potentiation. Using this approach, we have demonstrated that modulation of the MD can yield engineered variants with decreased off-target effects. © 2021 The Protein Society.

Author Keywords
alpha-synuclein;  amyloid;  fused in sarcoma;  Hsp104;  protein disaggregase;  protein misfolding;  TAR DNA-binding protein 43 (TDP-43)

Funding details
National Institutes of HealthNIH
National Institute of General Medical SciencesNIGMSR35GM128772

Document Type: Article
Publication Stage: Article in Press
Source: Scopus