Scopus list of publications for May 21, 2023
Circadian clock protein BMAL1 broadly influences autophagy and endolysosomal function in astrocytes
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (20), pp. e2220551120.
McKee, C.A.a b , Polino, A.J.c , King, M.W.a b , Musiek, E.S.a b
a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
b Center on Biological Rhythms and Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
c Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
Abstract
An emerging role for the circadian clock in autophagy and lysosome function has opened new avenues for exploration in the field of neurodegeneration. The daily rhythms of circadian clock proteins may coordinate gene expression programs involved not only in daily rhythms but in many cellular processes. In the brain, astrocytes are critical for sensing and responding to extracellular cues to support neurons. The core clock protein BMAL1 serves as the primary positive circadian transcriptional regulator and its depletion in astrocytes not only disrupts circadian function but also leads to a unique cell-autonomous activation phenotype. We report here that astrocyte-specific deletion of Bmal1 influences endolysosome function, autophagy, and protein degradation dynamics. In vitro, Bmal1-deficient astrocytes exhibit increased endocytosis, lysosome-dependent protein cleavage, and accumulation of LAMP1- and RAB7-positive organelles. In vivo, astrocyte-specific Bmal1 knockout (aKO) brains show accumulation of autophagosome-like structures within astrocytes by electron microscopy. Transcriptional analysis of isolated astrocytes from young and aged Bmal1 aKO mice indicates broad dysregulation of pathways involved in lysosome function which occur independently of TFEB activation. Since a clear link has been established between neurodegeneration and endolysosome dysfunction over the course of aging, this work implicates BMAL1 as a key regulator of these crucial astrocyte functions in health and disease.
Author Keywords
astrocyte; autophagy; Bmal1; circadian; lysosome
Document Type: Article
Publication Stage: Final
Source: Scopus
Increased Cognitive Effort Costs in Healthy Aging and Preclinical Alzheimer’s Disease
(2023) Psychology and Aging, .
Aschenbrenner, A.J.a , Crawford, J.L.b , Peelle, J.E.c , Fagan, A.M.a , Benzinger, T.L.S.d , Morris, J.C.a , Hassenstab, J.a b , Braver, T.S.b
a Department of Neurology, Washington University, St. Louis, United States
b Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
c Department of Otolaryngology, Washington University, St. Louis, United States
d Department of Radiology, Washington University, St. Louis, United States
Abstract
Life-long engagement in cognitively demanding activities may mitigate against declines in cognitive ability observed in healthy or pathological aging. However, the “mental costs” associated with completing cognitive tasks also increase with age and may be partly attributed to increases in preclinical levels of Alzheimer’s disease (AD) pathology, specifically amyloid. We test whether cognitive effort costs increase in a domaingeneral manner among older adults, and further, whether such age-related increases in cognitive effort costs are associated with working memory (WM) capacity or amyloid burden, a signature pathology of AD. In two experiments, we administered a behavioral measure of cognitive effort costs (cognitive effort discounting) to a sample of older adults recruited from online sources (Experiment 1) or from ongoing longitudinal studies of aging and dementia (Experiment 2). Experiment 1 compared age-related differences in cognitive effort costs across two domains,WMand speech comprehension. Experiment 2 compared cognitive effort costs between a group of participants who were rated positive for amyloid relative to those with no evidence of amyloid. Results showed age-related increases in cognitive effort costs were evident in both domains. Cost estimates were highly correlated between the WM and speech comprehension tasks but did not correlate with WM capacity. In addition, older adults who were amyloid positive had higher cognitive effort costs than those who were amyloid negative. Cognitive effort costs may index a domain-general trait that consistently increases in aging. Differences in cognitive effort costs associatedwith amyloid burden suggest a potential neurobiological mechanism for age-related differences © 2023 American Psychological Association
Author Keywords
aging; Alzheimer’s disease; amyloid; cognitive effort
Funding details
National Institute on AgingNIAP01-AG03991, P01-AG26276, P30-AG066444, P50-AG05681, R21-AG067295
National Institute of Neurological Disorders and StrokeNINDSR24-AG054355, T32-NS115672
Alzheimer’s AssociationAA2019-AARF-643898
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Open-source statistical and data processing tools for wide-field optical imaging data in mice
(2023) Neurophotonics, 10 (1), art. no. 016601, .
Brier, L.M.a , Culver, J.P.a b c d
a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Physics, Washington University School of Arts and Science, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University School of Engineering, St. Louis, MO, United States
d Department of Electrical and Systems Engineering, Washington University School of Engineering, St. Louis, MO, United States
Abstract
Significance: Wide-field optical imaging (WOI) can produce concurrent hemodynamic and cell-specific calcium recordings across the entire cerebral cortex in animal models. There have been multiple studies using WOI to image mouse models with various environmental or genetic manipulations to understand various diseases. Despite the utility of pursuing mouse WOI alongside human functional magnetic resonance imaging (fMRI), and the multitude of analysis toolboxes in the fMRI literature, there is not an available open-source, user-friendly data processing and statistical analysis toolbox for WOI data. Aim: To assemble a MATLAB toolbox for processing WOI data, as described and adapted to combine techniques from multiple WOI groups and fMRI. Approach: We outline our MATLAB toolbox on GitHub with multiple data analysis packages and translate a commonly used statistical approach from the fMRI literature to the WOI data. To illustrate the utility of our MATLAB toolbox, we demonstrate the ability of the processing and analysis framework to detect a well-established deficit in a mouse model of stroke and plot activation areas during an electrical paw stimulus experiment. Results: Our processing toolbox and statistical methods isolate a somatosensory-based deficit 3 days following photothrombotic stroke and cleanly localize sensory stimulus activations. Conclusions: The toolbox presented here details an open-source, user-friendly compilation of WOI processing tools with statistical methods to apply to any biological question investigated with WOI techniques. © The Authors.
Author Keywords
calcium imaging; data processing; optical imaging; wide-field imaging
Funding details
National Institutes of HealthNIHR01NS090874, R01NS099429
National Institute on AgingNIAF30AG061932
Document Type: Article
Publication Stage: Final
Source: Scopus
Skeletal muscle delimited myopathy and verapamil toxicity in SUR2 mutant mouse models of AIMS
(2023) EMBO Molecular Medicine, .
McClenaghan, C.a b , Mukadam, M.A.a , Roeglin, J.a , Tryon, R.C.a , Grabner, M.c , Dayal, A.c , Meyer, G.A.d , Nichols, C.G.a
a Center for the Investigation of Membrane Excitability Diseases, and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
b Center for Advanced Biotechnology and Medicine, and Departments of Pharmacology and Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
c Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
d Program in Physical Therapy, Departments of Orthopaedic Surgery, Neurology and Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
Abstract
ABCC9-related intellectual disability and myopathy syndrome (AIMS) arises from loss-of-function (LoF) mutations in the ABCC9 gene, which encodes the SUR2 subunit of ATP-sensitive potassium (KATP) channels. KATP channels are found throughout the cardiovascular system and skeletal muscle and couple cellular metabolism to excitability. AIMS individuals show fatigability, muscle spasms, and cardiac dysfunction. We found reduced exercise performance in mouse models of AIMS harboring premature stop codons in ABCC9. Given the roles of KATP channels in all muscles, we sought to determine how myopathy arises using tissue-selective suppression of KATP and found that LoF in skeletal muscle, specifically, underlies myopathy. In isolated muscle, SUR2 LoF results in abnormal generation of unstimulated forces, potentially explaining painful spasms in AIMS. We sought to determine whether excessive Ca2+ influx through CaV1.1 channels was responsible for myopathology but found that the Ca2+ channel blocker verapamil unexpectedly resulted in premature death of AIMS mice and that rendering CaV1.1 channels nonpermeable by mutation failed to reverse pathology; results which caution against the use of calcium channel blockers in AIMS. © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
Author Keywords
ABCC9; AIMS; myopathy; SUR2; verapamil
Funding details
National Institutes of HealthNIHR35 HL140024
American Heart AssociationAHA19POST34380407, K99/R00 HL150277
University of WashingtonUW
Musculoskeletal Research Center, Washington University in St. LouisMRC
Austrian Science FundFWFP23229‐B09, P27392‐B21
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Protein kinetics of superoxide dismutase-1 in familial and sporadic amyotrophic lateral sclerosis
(2023) Annals of Clinical and Translational Neurology, .
Ly, C.V.a , Ireland, M.D.a , Self, W.K.a , Bollinger, J.a , Jockel-Balsarotti, J.a , Herzog, H.a , Allred, P.a , Miller, L.b , Doyle, M.b , Anez-Bruzual, I.b , Trikamji, B.a , Hyman, T.a , Kung, T.a , Nicholson, K.b , Bucelli, R.C.a , Patterson, B.W.c , Bateman, R.J.a d e , Miller, T.M.a d
a Department of Neurology, Washington University, Saint Louis, MO, United States
b Sean M. Healey & AMG Center for ALS, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
c Department of Medicine, Washington University, Saint Louis, MO, United States
d Hope Center for Neurological Disorders, Washington University, Saint Louis, MO, United States
e Knight Alzheimer’s Disease Research Center, Washington University, Saint Louis, MO, United States
Abstract
Objective: Accumulation of misfolded superoxide dismutase-1 (SOD1) is a pathological hallmark of SOD1-related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. Methods: We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. Results: In participants with heterozygous SOD1A5V mutations, known to cause rapidly progressive ALS, mutant SOD1 protein exhibited ~twofold faster turnover and ~ 16-fold lower concentration compared to wild-type SOD1 protein. SDGPVKV levels were increased in SOD1A5V carriers relative to controls. Thus, SOD1 mutations impact protein kinetics and stability. We applied this approach to sporadic ALS participants and found that SOD1 turnover, concentration, and SDGPVKV levels are not significantly different compared to controls. Interpretation: These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. Trial Registration: Clinicaltrials.gov: NCT03449212. © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institutes of HealthNIHK08 NS107621, P30 DK056341, R01 NS097816
Biogen
Novartis Pharmaceuticals CorporationNPC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Brain age” predicts disability accumulation in multiple sclerosis
(2023) Annals of Clinical and Translational Neurology, .
Brier, M.R.a , Li, Z.a , Ly, M.b c , Karim, H.T.c d , Liang, L.e , Du, W.e , McCarthy, J.E.e , Cross, A.H.a , Benzinger, T.L.S.b , Naismith, R.T.a , Chahin, S.a
a Department of Neurology, Washington University in St. Louis, St Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St Louis, MO, United States
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
e Department of Mathematics and Statistics, Washington University in St. Louis, St Louis, MO, United States
Abstract
Objective: Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of “brain age” analysis on disability in MS using a large, real-world dataset. Methods: Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models. Results: MS was associated with advanced predicted brain age cross-sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability. Interpretation: Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation. © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institutes of HealthNIH2R25NS090978‐06, K01MH122741, KL2TR002346
Division of Mathematical SciencesDMS2054199, R01AG052550
Alzheimer’s AssociationAA
Bristol-Myers SquibbBMS
Biogen
Document Type: Article
Publication Stage: Article in Press
Source: Scopus