Hope Center member publications

BRAF mutations may identify a clinically distinct subset of glioblastoma
(2021) Scientific Reports, 11 (1), art. no. 19999, . 

McNulty, S.N.^a , Schwetye, K.E.^a , Ferguson, C.^a , Storer, C.E.^b , Ansstas, G.^c d , Kim, A.H.^d e , Gutmann, D.H.^f , Rubin, J.B.^d g h , Head, R.D.^b , Dahiya, S.^a d

^a Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States
^b Department of Genetics, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States
^c Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States
^d Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Prior studies examining the mutational landscape of GBM revealed recurrent alterations in genes that regulate the same growth control pathways. To this regard, ~ 40% of GBM harbor EGFR alterations, whereas BRAF variants are rare. Existing data suggests that gain-of-function mutations in these genes are mutually exclusive. This study was designed to explore the clinical, pathological, and molecular differences between EGFR- and BRAF-mutated GBM. We reviewed retrospective clinical data from 89 GBM patients referred for molecular testing between November 2012 and December 2015. Differences in tumor mutational profile, location, histology, and survival outcomes were compared in patients with EGFR- versus BRAF-mutated tumors, and microarray data from The Cancer Genome Atlas was used to assess differential gene expression between the groups. Individuals with BRAF-mutant tumors were typically younger and survived longer relative to those with EGFR-mutant tumors, even in the absence of targeted treatments. BRAF-mutant tumors lacked distinct histomorphology but exhibited unique localization in the brain, typically arising adjacent to the lateral ventricles. Compared to EGFR- and IDH1-mutant tumors, BRAF-mutant tumors showed increased expression of genes related to a trophoblast-like phenotype, specifically HLA-G and pregnancy specific glycoproteins, that have been implicated in invasion and immune evasion. Taken together, these observations suggest a distinct clinical presentation, brain location, and gene expression profile for BRAF-mutant tumors. Pending further study, this may prove useful in the stratification and management of GBM. © 2021, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

In vitro characterization of [3H]VAT in cells, animal and human brain tissues for vesicular acetylcholine transporter
(2021) European Journal of Pharmacology, 911, art. no. 174556, . 

Liang, Q.^a , Joshi, S.^a , Liu, H.^a , Yu, Y.^a , Zhao, H.^a , Benzinger, T.L.S.^a b , Perlmutter, J.S.^a b c , Tu, Z.^a

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neurology, Program in Occupational Therapy, Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Vesicular acetylcholine transporter plays a crucial role in the cholinergic system, and its alterations is implicated in several neurodegenerative disorders. We recently developed a PET imaging tracer [18F]VAT to target VAChT in vivo with high affinity and selectivity. Here we report in vitro characterization of [3H]VAT, a tritiated counterpart of [18F]VAT. Using human VAChT-rich cell membrane extracts, a saturated binding curve was obtained for [3H]VAT with Kd = 6.5 nM and Bmax = 22.89 pmol/mg protein. In the [3H]VAT competition-binding assay with a panel of CNS ligands, binding inhibition of [3H]VAT was observed using VAChT ligands, the Ki values ranged from 5.41 to 33.3 nM. No inhibition was detected using a panel of other CNS ligands. In vitro [3H]VAT autoradiography of rat brain sections showed strong signals in the striatum, moderate to high signals in vermis, thalamus, cortex, and hippocampus, and weak signals in cerebellum. Strong [3H]VAT ARG signals were also observed from striatal sections of normal nonhuman primates and human brains. Competitive ARG study with human striatal sections demonstrated strong ARG signals of [3H]VAT in caudate and putamen were blocked significantly by either VAChT ligand TZ659 or (−)-vesamicol, but not by the σ1 receptor ligand Yun-122. ARG study also indicated that signal in the striatal sections from PSP human brains was lower than normal human brains. These data provide solid evidence supporting [18F]VAT as a suitable PET radiotracer for quantitative assessment of VAChT levels in vivo. © 2021 Elsevier B.V.

Author Keywords
Autoradiography;  Binding assay;  Progressive supranuclear palsy;  Radioligand;  Striatum;  Vesicular acetylcholine transporter

Document Type: Article
Publication Stage: Final
Source: Scopus

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss
(2021) American Journal of Human Genetics, 108 (10), pp. 2006-2016. 

Richard, E.M.^a , Bakhtiari, S.^b c , Marsh, A.P.L.^b c , Kaiyrzhanov, R.^d , Wagner, M.^e f , Shetty, S.^b c , Pagnozzi, A.^g , Nordlie, S.M.^b c , Guida, B.S.^b c , Cornejo, P.^h i j , Magee, H.^b c , Liu, J.^b c , Norton, B.Y.^b c , Webster, R.I.^k , Worgan, L.^l , Hakonarson, H.^m , Li, J.ⁿ , Guo, Y.^o p , Jain, M.^q , Blesson, A.^r , Rodan, L.H.^s t , Abbott, M.-A.^u , Comi, A.^v w , Cohen, J.S.^v w , Alhaddad, B.^e , Meitinger, T.^e , Lenz, D.^x , Ziegler, A.^y , Kotzaeridou, U.^y , Brunet, T.^e , Chassevent, A.^v , Smith-Hicks, C.^v w , Ekstein, J.^z , Weiden, T.^aa , Hahn, A.^ab , Zharkinbekova, N.^ac , Turnpenny, P.^ad , Tucci, A.^ae , Yelton, M.^af , Horvath, R.^ag , Gungor, S.^ah , Hiz, S.^ai aj , Oktay, Y.^ai ak , Lochmuller, H.^al , Zollino, M.^am an , Morleo, M.^ao , Marangi, G.^am an , Nigro, V.^ao ap , Torella, A.^ao ap , Pinelli, M.^ao , Amenta, S.^am an , Husain, R.A.^aq , Grossmann, B.^ar , Rapp, M.^as , Steen, C.^at , Marquardt, I.^au , Grimmel, M.^ar , Grasshoff, U.^ar , Korenke, G.C.^au , Owczarek-Lipska, M.^av aw , Neidhardt, J.^av ax , Radio, F.C.^ay , Mancini, C.^ay , Claps Sepulveda, D.J.^ay , McWalter, K.^az , Begtrup, A.^az , Crunk, A.^az , Guillen Sacoto, M.J.^az , Person, R.^az , Schnur, R.E.^az , Mancardi, M.M.^ba , Kreuder, F.^bb , Striano, P.^bc bd , Zara, F.^bd be , Chung, W.K.^bf , Marks, W.A.^bg bh , van Eyk, C.L.^bi bj , Webber, D.L.^bi bj , Corbett, M.A.^bi bj , Harper, K.^bi bj , Berry, J.G.^bi bj , MacLennan, A.H.^bi bj , Gecz, J.^bi bj bk , Tartaglia, M.^ay , Salpietro, V.^bc bd , Christodoulou, J.^bl bm , Kaslin, J.^bb , Padilla-Lopez, S.^b c , Bilguvar, K.^bn bo , Munchau, A.^as , Ahmed, Z.M.^a bp , Hufnagel, R.B.^bq , Fahey, M.C.^br , Maroofian, R.^d , Houlden, H.^d , Sticht, H.^bs , Mane, S.M.^bn bo , Rad, A.^bt , Vona, B.^bt , Jin, S.C.^bu , Haack, T.B.^ar bv , Makowski, C.^bw , Hirsch, Y.^z , Riazuddin, S.^a bp , Kruer, M.C.^b c

^a Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, United States
^b Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, United States
^c Departments of Child Health, Neurology, Cellular, and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine – Phoenix, Phoenix, AZ 85004, United States
^d Department of Neuromuscular Disorders, Institute of Neurology, University College London, Queen Square, London, UK WC1N 3BG, United Kingdom
^e Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, 81675, Germany
^f Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, 85764, Germany
^g CSIRO Health and Biosecurity, The Australian e-Health Research Centre, Brisbane, QLD 4029, Australia
^h Pediatric Neuroradiology Division, Pediatric Radiology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ 85016, United States
ⁱ University of Arizona College of Medicine, Phoenix, AZ 85004, United States
^j Mayo Clinic, Scottsdale, AZ 85259, United States
^k Neurology Department, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia
^l Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
^m Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ⁿ Department of Computer Science, City University of Hong Kong, Kowloon, 999077, Hong Kong
^o Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^p Center for Data Driven Discovery in Biomedicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19146, United States
^q Department of Bone and Osteogenesis Imperfecta, Kennedy Krieger Institute, Baltimore, MD 21205, United States
^r Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, MD 21211, United States
^s Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
^t Department of Neurology, Boston Children’s Hospital, Boston, MA 02115, United States
^u University of Massachusetts Medical School – Baystate, Baystate Children’s Hospital, Springfield, MA 01107, United States
^v Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, United States
^w Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
^x Centre of Child and Adolescent Medicine, Department of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, Heidelberg, 69120, Germany
^y Department of Child Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
^z Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, New York, NY 11211, United States
^aa Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases9054020, Israel
^ab Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, 35392, Germany
^ac Department of Neurology, South Kazakhstan Medical Academy, Shymkent, 160001, Kazakhstan
^ad Clinical Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK EX1 2ED, United Kingdom
^ae Clinical Pharmacology, William Harvey Research Institute, Charterhouse Square, School of Medicine and Dentistry Queen Mary University of London, London, UK EC1M 6BQ, United Kingdom
^af Penn State Health Children’s Hospital, Hershey, PA 17033, United States
^ag Department of Clinical Neurosciences, John Van Geest Cambridge Centre for Brain Repair, University of Cambridge School of Clinical Medicine, Cambridge, UK CB2 0PY, United Kingdom
^ah Inonu University, Faculty of Medicine, Turgut Ozal Research Center, Department of Paediatric Neurology, Malatya, 44280, Turkey
^ai Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Izmir, 35340, Turkey
^aj Department of Pediatric Neurology, Faculty of Medicine, Dokuz Eylul University, Izmir, 35340, Turkey
^ak Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, 35220, Turkey
^al Children’s Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital, and Brain and Mind Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada
^am Università Cattolica Sacro Cuore, Facoltà di Medicina e Chirurgia, Dipartimento Scienze della Vita e Sanità Pubblica, Roma, 00168, Italy
^an Fondazione Policlinico A. Gemelli IRCCS, Sezione di Medicina Genomica, Roma, 00168, Italy
^ao Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, 80078, Italy
^ap Department of Precision Medicine, University of Campania “Luigi Vanvitelli,”, Naples, 80138, Italy
^aq Department of Neuropediatrics, Jena University Hospital, Jena, 07747, Germany
^ar Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tuebingen, 72076, Germany
^as Institute of Systems Motor Science, University of Lübeck, Lübeck, 23538, Germany
^at Department of Paediatric and Adolescent Medicine, St Joseph Hospital, Berlin, 12101, Germany
^au University Children’s Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, Oldenburg, 26133, Germany
^av Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, 26129, Germany
^aw Junior Research Group, Genetics of Childhood Brain Malformations, Faculty VI-School of Medicine and Health Sciences, University of Oldenburg, Oldenburg, 26129, Germany
^ax Research Center Neurosensory Science, University of Oldenburg, Oldenburg, 26129, Germany
^ay Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00146, Italy
^az GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, United States
^ba Unit of Child Neuropsichiatry, Department of Clinical and Surgical Neurosciences and Rehabilitation, IRCCS Giannina Gaslini, Genoa, 16147, Italy
^bb Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3168, Australia
^bc Pediatric Neurology and Muscular Diseases Unit, IRRCS Istituto Giannina Gaslini, Genoa, 16148, Italy
^bd Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 16142, Italy
^be Unit of Medical Genetics, IRRCS Istituto Giannina Gaslini, Genoa, 16147, Italy
^bf Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, United States
^bg Department of Neurology, Cook Children’s Medical Center, Fort Worth, TX 76104, United States
^bh Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
^bi Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5006, Australia
^bj Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia
^bk South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
^bl Brain and Mitochondrial Research Group, Murdoch Children’s Research Institute, Melbourne Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
^bm Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW 2006, Australia
^bn Yale Center for Genome Analysis, Yale University, New Haven, CT 06520, United States
^bo Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, United States
^bp Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, United States
^bq Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, United States
^br Department of Paediatrics, Monash University, Melbourne, VIC 3168, Australia
^bs Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
^bt Department of Otolaryngology – Head and Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University Tübingen, Tübingen, 72076, Germany
^bu Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^bv Centre for Rare Diseases, University of Tübingen, Tuebingen, 72074, Germany
^bw Department of Paediatrics, Adolescent Medicine and Neonatology, Munich Clinic, Schwabing Hospital and Technical University of Munich, School of Medicine, Munich, 80804, Germany

Abstract
Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype. © 2021

Author Keywords
AAA+ superfamily;  ATPase;  cerebral palsy;  epilepsy;  intellectual disability;  movement disorder;  neurodevelopmental disorder;  sensorineural hearing loss;  SPATA5L1

Document Type: Article
Publication Stage: Final
Source: Scopus

Comparison of hippocampal subfield segmentation agreement between 2 automated protocols across the adult life span
(2021) American Journal of Neuroradiology, 42 (10), pp. 1783-1789. 

Samara, A.^a , Raji, C.A.^b c , Li, Z.^a d , Hershey, T.^a b c

^a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Psychological and Brain Sciences, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND AND PURPOSE: The hippocampus is a frequent focus of quantitative neuroimaging research, and structural hippocampal alterations are related to multiple neurocognitive disorders. An increasing number of neuroimaging studies are focusing on hippocampal subfield regional involvement in these disorders using various automated segmentation approaches. Direct comparisons among these approaches are limited. The purpose of this study was to compare the agreement between two automated hippocampal segmentation algorithms in an adult population. MATERIALS AND METHODS: We compared the results of 2 automated segmentation algorithms for hippocampal subfields (FreeSurfer v6.0 and volBrain) within a single imaging data set from adults (n ¼ 176, 89 women) across a wide age range (20-79 years). Brain MR imaging was acquired on a single 3T scanner as part of the IXI Brain Development Dataset and included T1- and T2-weighted MR images. We also examined subfield volumetric differences related to age and sex and the impact of different intracranial volume and total hippocampal volume normalization methods. RESULTS: Estimated intracranial volume and total hippocampal volume of both protocols were strongly correlated (r ¼ 0.93 and 0.9, respectively; both P,.001). Hippocampal subfield volumes were correlated (ranging from r ¼ 0.42 for the subiculum to r ¼ 0.78 for the cornu ammonis [CA]1, all P,.001). However, absolute volumes were significantly different between protocols. volBrain produced larger CA1 and CA4-dentate gyrus and smaller CA2-CA3 and subiculum volumes compared with FreeSurfer v6.0. Regional age- and sex-related differences in subfield volumes were qualitatively and quantitatively different depending on segmentation protocol and intracranial volume/total hippocampal volume normalization method. CONCLUSIONS: The hippocampal subfield volume relationship to demographic factors and disease states should undergo nuanced interpretation, especially when considering different segmentation protocols. © 2021 American Society of Neuroradiology. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
(2021) Science Translational Medicine, 13 (613), art. no. eabc9375, . 

Liu, C.-C.^a , Murray, M.E.^a , Li, X.^a , Zhao, N.^a , Wang, N.^a , Heckman, M.G.^b , Shue, F.^a , Martens, Y.^a , Li, Y.^a , Raulin, A.-C.^a , Rosenberg, C.L.^a , Doss, S.V.^a , Zhao, J.^a , Wren, M.C.^a , Jia, L.^a , Ren, Y.^b , Ikezu, T.C.^a , Lu, W.^a , Fu, Y.^a , Caulfield, T.^a , Trottier, Z.A.^a , Knight, J.^a , Chen, Y.^a , Linares, C.^a , Wang, X.^b , Kurti, A.^a , Asmann, Y.W.^b , Wszolek, Z.K.^c , Smith, G.E.^d , Vemuri, P.^e , Kantarci, K.^e , Knopman, D.S.^f , Lowe, V.J.^e , Jack, C.R., Jr.^e , Parisi, J.E.^f g , Ferman, T.J.^h , Boeve, B.F.^f , Graff-Radford, N.R.^c , Petersen, R.C.^f , Younkin, S.G.^a , Fryer, J.D.ⁱ , Wang, H.^j , Han, X.^j k , Frieden, C.^l , Dickson, D.W.^a , Ross, O.A.^a m , Bu, G.^a

^a Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
^b Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, United States
^c Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, United States
^d Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, United States
^e Department of Radiology, Mayo Clinic, Rochester, MN 55905, United States
^f Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States
^g Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States
^h Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, United States
ⁱ Department of Neuroscience, Mayo Clinic, Scottsdale, AZ 85259, United States
^j Barshop Institute for Longevity and Aging Studies, San Antonio, TX 78229, United States
^k Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States
^l Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63110, United States
^m Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, United States

Abstract
Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB. Copyright © 2021 The Authors, some rights reserved;

Document Type: Article
Publication Stage: Final
Source: Scopus

Noise Exposure Potentiates Exocytosis From Cochlear Inner Hair Cells
(2021) Frontiers in Synaptic Neuroscience, 13, art. no. 740368, . 

Boero, L.E.^a b d , Payne, S.^c , Gómez-Casati, M.E.^b , Rutherford, M.A.^c , Goutman, J.D.^a

^a Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres” (INGEBI), Buenos Aires, Argentina
^b Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
^c Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
^d Luis E. Boero, Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, United States

Abstract
Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15–16 were exposed to 1–12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔCm showed the typical bell-shaped curve that mirrors the voltage dependence of Ca2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca2+ influx, suggesting a modification in coupling between Ca2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca2+-dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 (Vglut3) knock-out (KO) mice. Unlike WT, IHCs from Vglut3KO mice showed a noise-induced reduction in ΔCm and Ca2+ influx with no change in the Ca2+-dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3-dependent potentiation of exocytosis. © Copyright © 2021 Boero, Payne, Gómez-Casati, Rutherford and Goutman.

Author Keywords
exocytosis;  hair cells;  noise exposure;  synapse loss;  Vglut3KO

Document Type: Article
Publication Stage: Final
Source: Scopus

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair
(2021) eLife, 10, art. no. e68457, . 

Avraham, O.^a , Feng, R.^a , Ewan, E.E.^a , Rustenhoven, J.^b c , Zhao, G.^a b , Cavalli, V.^a d e

^a Department of Neuroscience, Washington University School of Medicine, Saint Louis, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
^c Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St Louis, United States
^d Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, United States

Abstract
Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease. © 2021, eLife Sciences Publications Ltd. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Cerebral Oxygen Metabolic Stress, Microstructural Injury, and Infarction in Adults With Sickle Cell Disease
(2021) Neurology, 97 (9), pp. e902-e912. 

Wang, Y., Fellah, S., Fields, M.E., Guilliams, K.P., Binkley, M.M., Eldeniz, C., Shimony, J.S., Reis, M., Vo, K.D., Chen, Y., Lee, J.-M., An, H., Ford, A.L.

From the Department of Neurology (Y.W., S.F., M.M.B., J.-M.L., H.A., A.L.F.), Division of Pediatric Hematology/Oncology (M.E.F.), Division of Pediatric Neurology (K.P.G.), and Mallinckrodt Institute of Radiology (C.E., J.S.S., M.R., K.D.V., Y.C., J.-M.L., H.A., A.L.F.), Washington University School of Medicine, St. Louis, MO

Abstract
OBJECTIVE: To determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD). METHODS: Control participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location. RESULTS: Of 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g, p < 0.001), increased OEF (0.35 vs 0.25, p < 0.001), increased MD (0.76 vs 0.72 × 10-3 mm2s-1, p = 0.005), and decreased FA (0.40 vs 0.42, p = 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (β = 0.19, p = 0.035), but not CBF (β = 0.00, p = 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort. CONCLUSION: Elevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Document Type: Note
Publication Stage: Final
Source: Scopus

IL-33 signaling in sensory neurons promotes dry skin itch
(2021) Journal of Allergy and Clinical Immunology, .

Trier, A.M.^a b , Mack, M.R.^a b , Fredman, A.^a b , Tamari, M.^a b , Ver Heul, A.M.^a c , Zhao, Y.^a d , Guo, C.J.^a d , Avraham, O.^e , Ford, Z.K.^j , Oetjen, L.K.^a b , Feng, J.^a d , Dehner, C.^b , Coble, D.^f , Badic, A.^a b , Joshita, S.^k , Kubo, M.^l m , Gereau, R.W., IV^d e g , Alexander-Brett, J.^h , Cavalli, V.^e , Davidson, S.^j , Hu, H.^a d , Liu, Q.^a d , Kim, B.S.^a b d i

^a Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St Louis, Mo, United States
^b Division of Dermatology, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
^c Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
^d Department of Anesthesiology, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
^e Department of Neuroscience, Washington University School of Medicine, St Louis, Mo, United States
^f Division of Biostatistics, Washington University School of Medicine, St Louis, Mo, United States
^g Washington University Pain Center, Washington University School of Medicine, St Louis, Mo, United States
^h Division of Pulmonary and Critical Care, Department of Medicine, Washington University School of Medicine, St Louis, Mo, United States
ⁱ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Mo, United States
^j Department of Anesthesiology and Neuroscience Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^k Division of Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Nagano, Japan
^l Laboratory of Cytokine Regulation, Center for Integrative Medical Science (IMS), RIKEN Yokohama Institute, Yokohama, Japan
^m Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Tokyo, Japan

Abstract
Background: Chronic pruritus, or itch, is common and debilitating, but the neuroimmune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron–restricted activity of IL-33 is necessary for chronic itch remains poorly understood. Objectives: We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models. Methods: Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively. Results: IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology. Conclusions: These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight into future therapeutic strategies targeting the IL-33 pathway for chronic itch. © 2021 The Authors

Author Keywords
Atopic dermatitis;  chronic pruritus of unknown origin;  dry skin;  IL-33;  itch;  neuroimmunology;  pruriceptor;  pruritogen

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

Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP
(2021) Autophagy, . 

Wani, A.^a b , Weihl, C.C.^a

^a Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, United States

Abstract
VCP (valosin containing protein), a member of the AAA+ protein family, is critical for many cellular processes and functions. Dominant VCP mutations cause a rare neurodegenerative disease known as multisystem proteinopathy (MSP). The spectrum of mechanisms causing fronto-temporal dementia with TARDBP/TDP-43 inclusions (FTLD-TARDBP) by VCP disease mutations remains unclear. Our recent work identified VCP activity as a mediator of FTLD-TARDBP. Specifically, brain atrophy, behavioral changes, neuronal loss, gliosis, and TARDBP pathology were observed in vcp conditional knockout (cKO) mice. We also found that autophago-lysosomal dysfunction, TARDBP inclusions, and ubiquitin-proteasome impairment precede neuronal loss. We further studied conditional expression of the disease-associated mutation VCPR155C in vcp-null mice. We observed features similar to those of VCP inactivation, suggesting that VCP mutation is hypomorphic. Furthermore, proteomic, and transcriptomic signatures in vcp cKO mice resemble those of GRN/Progranulin carriers. Therefore, VCP is essential for neuronal survival by several mechanisms and could be a therapeutic target aimed at restoring protein homeostasis in patients with FTLD-TARDBP. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Autophagy;  FTLD-TDP-43;  neurodegeneration;  progranulin;  valosin-containing protein

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