List of publications for week of May 19, 2022
SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers
(2022) Neurobiology of Disease, 169, art. no. 105737, .
Norambuena, A.a , Sun, X.a , Wallrabe, H.a , Cao, R.a d , Sun, N.f , Pardo, E.a , Shivange, N.a , Wang, D.B.a , Post, L.A.c e , Ferris, H.A.c e , Hu, S.f , Periasamy, A.a d , Bloom, G.S.a b c
a Department of Biology, University of Virginia, Charlottesville, VA 22904, United States
b Department of Cell Biology, University of Virginia, Charlottesville, VA 22904, United States
c Department of Neuroscience, University of Virginia, Charlottesville, VA 22904, United States
d W.M. Keck Center for Cellular Imaging, University of Virginia, Charlottesville, VA 22904, United States
e Division of Endocrinology & Metabolism, School of Medicine, University of Virginia, Charlottesville, VA 22904, United States
f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Altered mitochondrial DNA (mtDNA) occurs in neurodegenerative disorders like Alzheimer’s disease (AD); how mtDNA synthesis is linked to neurodegeneration is poorly understood. We previously discovered Nutrient-induced Mitochondrial Activity (NiMA), an inter-organelle signaling pathway where nutrient-stimulated lysosomal mTORC1 activity regulates mtDNA replication in neurons by a mechanism sensitive to amyloid-β oligomers (AβOs), a primary factor in AD pathogenesis (Norambuena et al., 2018). Using 5-ethynyl-2′-deoxyuridine (EdU) incorporation into mtDNA of cultured neurons, along with photoacoustic and mitochondrial metabolic imaging of cultured neurons and mouse brains, we show these effects being mediated by mTORC1-catalyzed T40 phosphorylation of superoxide dismutase 1 (SOD1). Mechanistically, tau, another key factor in AD pathogenesis and other tauopathies, reduced the lysosomal content of the tuberous sclerosis complex (TSC), thereby increasing NiMA and suppressing SOD1 activity and mtDNA synthesis. AβOs inhibited these actions. Dysregulation of mtDNA synthesis was observed in fibroblasts derived from tuberous sclerosis (TS) patients, who lack functional TSC and elevated SOD1 activity was also observed in human AD brain. Together, these findings imply that tau and SOD1 couple nutrient availability to mtDNA replication, linking mitochondrial dysfunction to AD. © 2022 The Authors
Author Keywords
Alzheimer’s disease; Amino acids; Insulin; mTOR; Tau
Funding details
17–5
OD016446
National Institutes of HealthNIH
National Institute on AgingNIAR01AG067048
Alzheimer’s AssociationAAZEN-16-363266
Cure Alzheimer’s FundCAF
University of VirginiaUV
Geological Survey of BelgiumGSBRF1 AG051085
Document Type: Article
Publication Stage: Final
Source: Scopus
Sleep behavior and chronotype before and throughout pregnancy
(2022) Sleep Medicine, 94, pp. 54-62.
Zhao, P.a , Bedrick, B.S.a , Brown, K.E.a , McCarthy, R.a , Chubiz, J.E.a , Ju, Y.-E.S.a , Raghuraman, N.a , Fay, J.C.b , Jungheim, E.S.c , Herzog, E.D.a , England, S.K.a
a Washington University, St. Louis, United States
b University of Rochester, United States
c Northwestern University, United States
Abstract
Study objective: To compare sleep behavior before and during pregnancy. Methods: In this prospective cohort study, healthy women were followed from pre-pregnancy until delivery. At pre-pregnancy and each trimester, participants completed validated questionnaires of chronotype and sleep quality and timing, including the Munich ChronoType Questionnaire, Epworth Sleepiness Scale, and Pittsburgh Sleep Quality Index. The primary outcomes were sleep period start and end times, sleep duration, sleep midpoint, and social jetlag, compared between pre-pregnancy and each trimester. Wrist actigraphy was used to measure the same outcomes in a subset of participants. Results: Eighty-six women were included in analysis of questionnaires. Of these, 37 provided complete actigraphy data. Questionnaire and actigraphy data indicate that participants had less social jetlag during pregnancy than before pregnancy. Sleep period start times were earlier on both work and free days in the first and second trimesters than pre-pregnancy, and returned to pre-pregnancy times by the third trimester. Actigraphy data revealed that, compared to pre-pregnancy, participants had longer sleep periods in all trimesters on work days and in the first trimester on free days. Sleep surveys revealed that participants had poorer sleep quality in the first and third trimesters and more sleepiness in the first trimester than pre-pregnancy. Conclusion: The first trimester of pregnancy is characterized by earlier sleep period start time, longer sleep duration, and poorer sleep quality than pre-pregnancy. Sleep quality temporarily improves in the second trimester, and sleep period start time returns to pre-pregnancy time by the third trimester. Study rationale: Multiple parameters of sleep have been studied in the context of pregnancy and pregnancy outcomes, but rarely in comparison to pre-pregnancy or longitudinally through pregnancy. Study impact: Actigraphy and questionnaire data reveal sleep timing and quality change throughout pregnancy. These data on sleep changes in healthy pregnancy can be used as a baseline to identify sleep-related risk factors throughout pregnancy. © 2022 Elsevier B.V.
Author Keywords
Actigraphy; Chronotype; Circadian; Pregnancy; Reproduction; Sleep behavior; Sleep surveys; Survey
Funding details
National Institutes of HealthNIHK23NS089922, UL1RR024992 Sub-Award KL2TR000450
March of Dimes FoundationMDF
National Center for Advancing Translational SciencesNCATS
Institute of Clinical and Translational SciencesICTSUL1TR000448
Document Type: Article
Publication Stage: Final
Source: Scopus
Oxygen Metabolic Stress and White Matter Injury in Patients with Cerebral Small Vessel Disease
(2022) Stroke, 53 (5), pp. 1570-1579. Cited 1 time.
Kang, P.a , Ying, C.c , Chen, Y.a , Ford, A.L.a b , An, H.a b c , Lee, J.-M.a b c
a Department of Neurology, Washington University School of Medicine, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, United States
c Department of Biomedical Engineering, Washington University, United States
Abstract
Background: Chronic hypoxia-ischemia is a putative mechanism underlying the development of white matter hyperintensities (WMH) and microstructural disruption in cerebral small vessel disease. WMH fall primarily within deep white matter (WM) watershed regions. We hypothesized that elevated oxygen extraction fraction (OEF), a signature of hypoxia-ischemia, would be detected in the watershed where WMH density is highest. We further hypothesized that OEF would be elevated in regions immediately surrounding WMH, at the leading edge of growth. Methods: In this cross-sectional study conducted from 2016 to 2019 at an academic medical center in St Louis, MO, participants (age >50) with a range of cerebrovascular risk factors underwent brain magnetic resonance imaging using pseudocontinuous arterial spin labeling, asymmetric spin echo, fluid-attenuated inversion recovery and diffusion tensor imaging to measure cerebral blood flow (CBF), OEF, WMH, and WM integrity, respectively. We defined the physiologic watershed as a region where CBF was below the 10th percentile of mean WM CBF in a young healthy cohort. We conducted linear regression to evaluate the relationship between CBF and OEF with structural and microstructural WM injury defined by fluid-attenuated inversion recovery WMH and diffusion tensor imaging, respectively. We conducted ANOVA to determine if OEF was increased in proximity to WMH lesions. Results: In a cohort of 42 participants (age 50-80), the physiologic watershed region spatially overlapped with regions of highest WMH lesion density. As CBF decreased and OEF increased, WMH density increased. Elevated watershed OEF was associated with greater WMH burden and microstructural disruption, after adjusting for vascular risk factors. In contrast, WM and watershed CBF were not associated with WMH burden or microstructural disruption. Moreover, OEF progressively increased while CBF decreased, in concentric contours approaching WMH lesions. Conclusions: Chronic hypoxia-ischemia in the watershed region may contribute to cerebral small vessel disease pathogenesis and development of WMH. Watershed OEF may hold promise as an imaging biomarker to identify individuals at risk for cerebral small vessel disease progression. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
cerebral small vessel diseases; dementia; ischemia; leukoaraiosis; magnetic resonance imaging
Funding details
National Institutes of HealthNIHKL2 TR002346
American Academy of NeurologyAAN1P30NS098577, 1R011NS082561, R01HL129241, R01NS085419, RF1NS116565, U24 NS107230
National Center for Advancing Translational SciencesNCATS
Document Type: Article
Publication Stage: Final
Source: Scopus
Molecular and neural basis of pleasant touch sensation
(2022) Science, 376 (6592), pp. 483-491.
Liu, B.a , Qiao, L.a , Liu, K.a , Liu, J.a , Piccinni-Ash, T.J.a , Chen, Z.-F.a b
a Center for the Study of Itch and Sensory Disorders, Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
b Department of Medicine, Psychiatry, and Developmental Biology, Washington University, School of Medicine, St. Louis, MO 63110, United States
Abstract
Pleasant touch provides emotional and psychological support that helps mitigate social isolation and stress. However, the underlying mechanisms remain poorly understood. Using a pleasant touch-conditioned place preference (PT-CPP) test, we show that genetic ablation of spinal excitatory interneurons expressing prokineticin receptor 2 (PROKR2), or its ligand PROK2 in sensory neurons, abolishes PT-CPP without impairing pain and itch behaviors in mice. Mutant mice display profound impairments in stress response and prosocial behaviors. Moreover, PROKR2 neurons respond most vigorously to gentle stroking and encode reward value. Collectively, we identify PROK2 as a long-sought neuropeptide that encodes and transmits pleasant touch to spinal PROKR2 neurons. These findings may have important implications for elucidating mechanisms by which pleasant touch deprivation contributes to social avoidance behavior and mental disorders. Copyright © 2022 The Authors
Funding details
National Institutes of HealthNIH1R01AR056318-06, R01NS094344
Document Type: Article
Publication Stage: Final
Source: Scopus
Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity
(2022) Journal of Alzheimer’s Disease, 86 (4), pp. 1831-1848.
Rahmani, F.a , Wang, Q.a , Mckay, N.S.a , Keefe, S.a , Hantler, N.a , Hornbeck, R.a , Wang, Y.a , Hassenstab, J.a , Schindler, S.a b , Xiong, C.a , Morris, J.C.a b c , Benzinger, T.L.S.a c , Raji, C.A.a b
a Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC), Washington University, St. Louis, MO, United States
Abstract
Background: Obesity is an increasingly recognized modifiable risk factor for Alzheimer’s disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. Objective: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. Methods: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. Results: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. Conclusion: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD. © 2022 The authors.
Author Keywords
Aging; Alzheimer’s disease; body mass index; connectome; diffusion magnetic resonance imaging; white matter
Funding details
National Institutes of HealthNIH1RF1AG072637-01, EB009352, K23AG053426, P01AG 026276, P01AG003991, P30AG0 66444, P30NS098577, R01AG054567-01A1, UL1TR000448
Radiological Society of North AmericaRSNA
Foundation for Barnes-Jewish HospitalFBJH
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Final
Source: Scopus