List of publications for November 6, 2022
Pooled image-base screening of mitochondria with microraft isolation distinguishes pathogenic mitofusin 2 mutations
(2022) Communications Biology, 5 (1), art. no. 1128, .
Yenkin, A.L.a b , Bramley, J.C.a b , Kremitzki, C.L.a b , Waligorski, J.E.a b , Liebeskind, M.J.a b , Xu, X.E.a b , Chandrasekaran, V.D.a b , Vakaki, M.A.a b , Bachman, G.W.a b , Mitra, R.D.a b , Milbrandt, J.D.a b , Buchser, W.J.a b
a Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
b Functional Imaging for Variant Elucidation at the McDonnell Genome Institute, St Louis, MO, United States
Abstract
Most human genetic variation is classified as variants of uncertain significance. While advances in genome editing have allowed innovation in pooled screening platforms, many screens deal with relatively simple readouts (viability, fluorescence) and cannot identify the complex cellular phenotypes that underlie most human diseases. In this paper, we present a generalizable functional genomics platform that combines high-content imaging, machine learning, and microraft isolation in a method termed “Raft-Seq”. We highlight the efficacy of our platform by showing its ability to distinguish pathogenic point mutations of the mitochondrial regulator Mitofusin 2, even when the cellular phenotype is subtle. We also show that our platform achieves its efficacy using multiple cellular features, which can be configured on-the-fly. Raft-Seq enables a way to perform pooled screening on sets of mutations in biologically relevant cells, with the ability to physically capture any cell with a perturbed phenotype and expand it clonally, directly from the primary screen. © 2022, The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Autosomal dominant and sporadic late onset Alzheimer’s disease share a common in vivo pathophysiology
(2022) Brain: A Journal of Neurology, 145 (10), pp. 3594-3607.
Morris, J.C.a , Weiner, M.b , Xiong, C.c , Beckett, L.d , Coble, D.c , Saito, N.d , Aisen, P.S.e , Allegri, R.f , Benzinger, T.L.S.g , Berman, S.B.h , Cairns, N.J.i , Carrillo, M.C.j , Chui, H.C.e , Chhatwal, J.P.k , Cruchaga, C.l , Fagan, A.M.a , Farlow, M.m , Fox, N.C.n , Ghetti, B.o , Goate, A.M.p , Gordon, B.A.g , Graff-Radford, N.q , Day, G.S.q , Hassenstab, J.a , Ikeuchi, T.r , Jack, C.R.s , Jagust, W.J.t , Jucker, M.u v , Levin, J.w , Massoumzadeh, P.g , Masters, C.L.x , Martins, R.y , McDade, E.a , Mori, H.z , Noble, J.M.aa , Petersen, R.C.ab , Ringman, J.M.e , Salloway, S.ac , Saykin, A.J.ad , Schofield, P.R.ae , Shaw, L.M.af , Toga, A.W.ag , Trojanowski, J.Q.ah , Vöglein, J.ai , Weninger, S.aj , Bateman, R.J.a , Buckles, V.D.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, University of California at San Francisco, San Francisco, CA, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Public Health Sciences, School of Medicine, University of California; Davis, Davis, CA, USA
e Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
f Department of Cognitive Neurology, Neuropsychology and Neuropsychiatry, Institute for Neurological Research (FLENI)Buenos Aires, Argentina
g Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
h Department of Neurology and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, United States
i College of Medicine and Health and the Living Systems Institute, University of Exeter, Exeter, United Kingdom
j Alzheimer’s Association, Chicago, IL, United States
k Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
l Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
m Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
n Department of Neurodegenerative Disease and UK Dementia Research Institute, UCL Institute of Neurology, London, United Kingdom
o Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
p Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
q Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
r Department of Molecular Genetics, Brain Research Institute, Niigata UniversityNiigata, Japan
s Department of Radiology, Mayo Clinic, Rochester, MN, United States
t Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States
u Cell Biology of Neurological Diseases Group, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
v Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
w DZNE Munich, Munich Cluster of Systems Neurology (SyNergy) and Ludwig-Maximilians-Universität, Munich, Germany
x Florey Institute, University of Melbourne, Melbourne, Australia
y Sir James McCusker Alzheimer’s Disease Research Unit, Edith Cowan University, Nedlands, Australia
z Department of Neuroscience, Osaka City University Medical School, Japan
aa Department of Neurology, Taub Institute for Research on Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
ab Department of Neurology, Mayo Clinic, Rochester, MN, United States
ac Department of Neurology, Butler Hospital and Alpert Medical School of Brown University, Providence, RI 02906, United States
ad Department of Radiology and Imaging Sciences and the Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, United States
ae Neuroscience Research Australia and School of Medical Sciences, University of New South Wales, Sydney, Australia
af Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ag Laboratory of Neuro Imaging, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
ah Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ai German Center for Neurodegenerative Diseases (DZNE) and Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
aj Cambridge, MA, United States
Abstract
The extent to which the pathophysiology of autosomal dominant Alzheimer’s disease corresponds to the pathophysiology of ‘sporadic’ late onset Alzheimer’s disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer’s disease to late onset Alzheimer’s disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer’s disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer’s Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer’s disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer’s disease and late onset Alzheimer’s disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer’s disease than in late onset Alzheimer’s disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer’s disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer’s disease and late onset Alzheimer’s disease, supporting a shared pathobiological construct. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
Alzheimer pathophysiology; biomarkers; rates of change
Document Type: Article
Publication Stage: Final
Source: Scopus
Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy
(2022) Nature Neuroscience, .
Oh, Y.M.a , Lee, S.W.a , Kim, W.K.a , Chen, S.a , Church, V.A.a , Cates, K.a , Li, T.a b , Zhang, B.a b , Dolle, R.E.c , Dahiya, S.d , Pak, S.C.e , Silverman, G.A.e , Perlmutter, D.H.e , Yoo, A.S.a b
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biochemistry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which aging drives the onset of neurodegeneration in patients with HD remains unclear. In this study we examined striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD to model the age-dependent onset of pathology. We found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. We observed age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs and identified miR-29b-3p, whose age-associated upregulation promotes HD-MSN degeneration by impairing autophagic function through human-specific targeting of the STAT3 3′ untranslated region. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. Our results demonstrate miRNA upregulation with aging in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
National Institute on AgingNIAR01NS107488
National Institute of Neurological Disorders and StrokeNINDS
Hereditary Disease FoundationHDFRF1AG056296
Cure Alzheimer’s FundCAF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Perinatal oxycodone exposure causes long-term sex-dependent changes in weight trajectory and sensory processing in adult mice
(2022) Psychopharmacology, .
Minakova, E.a , Mikati, M.O.b c d e f , Madasu, M.K.d e f , Conway, S.M.d e f , Baldwin, J.W.c g , Swift, R.G.b h , McCullough, K.B.b h , Dougherty, J.D.b h i , Maloney, S.E.b i , Al-Hasani, R.c d e f
a Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Campus Box 8232, 660 South Euclid Avenue, St. Louis, MO 63110-1093, United States
c Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
e Washington University Pain Management Center, Washington University School of Medicine, St. Louis, MO, United States
f Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St. Louis, St. Louis, MO, United States
g Department of Biology, Washington University School of Medicine, St. Louis, MO, United States
h Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
i Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Rationale: In utero opioid exposure is associated with lower weight and a neonatal opioid withdrawal syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparing in utero only opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Objectives: Here, we sought to understand the impact of continued postnatal opioid exposure on long term behavioral consequences. Methods: We implemented a rodent perinatal opioid exposure model of oxycodone (Oxy) exposure that included Oxy exposure until birth (short Oxy) and continued postnatal opioid exposure (long Oxy) spanning gestation through birth and lactation. Results: Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following short or long Oxy exposure. Conclusions: Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Author Keywords
Neonatal opioid withdrawal syndrome; Nociceptive processing; Opioid; Oxycodone; Sex differences
Funding details
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATSULITR002345
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD103525
Washington University School of Medicine in St. LouisWUSM20–186-9770
Document Type: Article
Publication Stage: Article in Press
Source: Scopus