Subcellular pathways through VGluT3-expressing mouse amacrine cells provide locally tuned object-motion-selective signals in the retina
(2024) Nature Communications, 15 (1), art. no. 2965, .
Friedrichsen, K.a b c d , Hsiang, J.-C.a b c d , Lin, C.-I.a b c d , McCoy, L.a b c , Valkova, K.a b c , Kerschensteiner, D.a b c , Morgan, J.L.a b c
a Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Graduate Program in Neuroscience, Washington University in St. Louis, St. Louis, United States
Abstract
VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells (RGCs, outputs). Because these input and output connections are intermixed on the same dendrites, making sense of VG3 circuitry requires comparing the distribution of synapses across their arbors to the subcellular flow of signals. Here, we combine subcellular calcium imaging and electron microscopic connectomic reconstruction to analyze how VG3s integrate and transmit visual information. VG3s receive inputs from all nearby bipolar cell types but exhibit a strong preference for the fast type 3a bipolar cells. By comparing input distributions to VG3 dendrite responses, we show that VG3 dendrites have a short functional length constant that likely depends on inhibitory shunting. This model predicts that RGCs that extend dendrites into the middle layers of the inner plexiform encounter VG3 dendrites whose responses vary according to the local bipolar cell response type. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient
(2024) Cell, 187 (8), pp. 1889-1906.e24.
King, M.R.a b , Ruff, K.M.a b , Lin, A.Z.a b , Pant, A.a b , Farag, M.a b , Lalmansingh, J.M.a b , Wu, T.b c , Fossat, M.J.a b , Ouyang, W.d e f , Lew, M.D.b c , Lundberg, E.d e f , Vahey, M.D.a b , Pappu, R.V.a b
a Department of Biomedical Engineering, James McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Center for Biomolecular Condensates, James McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Electrical and Systems Engineering, James F. McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Bioengineering, Schools of Engineering and Medicine, Stanford University, Stanford, CA, United States
e Department of Pathology, School of Medicine, Stanford University, Stanford, CA, United States
f Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH—Royal Institute of Technology, Stockholm, Sweden
Abstract
Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed by E-rich regions, as defining features of nucleolar proteins. We show that the localization preferences of nucleolar proteins are determined by their IDRs and the types of RNA or DNA binding domains they encompass. In vitro reconstitutions and studies in cells showed how condensation, which combines binding and complex coacervation of nucleolar components, contributes to nucleolar organization. D/E tracts of nucleolar proteins contribute to lowering the pH of co-condensates formed with nucleolar RNAs in vitro. In cells, this sets up a pH gradient between nucleoli and the nucleoplasm. By contrast, juxta-nucleolar bodies, which have different macromolecular compositions, featuring protein IDRs with very different charge profiles, have pH values that are equivalent to or higher than the nucleoplasm. Our findings show that distinct compositional specificities generate distinct physicochemical properties for condensates. © 2024 The Author(s)
Author Keywords
biomolecular condensates; Cajal bodies; condensation; emergent property; evolution; interphase; nuclear speckles; nucleolus; pH; phase separation; proton motive force; reconstitution
Document Type: Article
Publication Stage: Final
Source: Scopus
CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly
(2024) Science Advances, 10 (14), art. no. eadk3674, .
Shue, F.a , White, L.J.b , Hendrix, R.D.c , Ulrich, J.c , Henson, R.L.c , Knight, W.c , Martens, Y.A.a , Wang, N.a , Roy, B.a , Starling, S.C.a , Ren, Y.b , Xiong, C.d , Asmann, Y.W.b , Syrjanen, J.A.e , Vassilaki, M.e , Mielke, M.M.e , Timsina, J.f , Sung, Y.J.f , Cruchaga, C.f , Holtzman, D.M.c , Bu, G.a , Petersen, R.C.g , Heckman, M.G.b , Kanekiyo, T.a
a Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
b Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, United States
c Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 93110, United States
e Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 93110, United States
g Departments of neurology, Mayo Clinic, Rochester, MN 55905, United States
Abstract
The immune system substantially influences age-related cognitive decline and Alzheimer’s disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly. © 2024 American Association for the Advancement of Science. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Patient and caregiver perceptions of Chiari malformation: a qualitative analysis of online discussion boards
(2024) Journal of Neurosurgery: Pediatrics, 33 (4), pp. 382-389.
Koller, G.M., Kann, M.R., Pugazenthi, S., Koneru, S., Bhavsar, S., Strahle, J.M.
Department of Neurosurgery, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
OBJECTIVE Patients and their caregivers utilize online discussion board forums as a means to seek and exchange information about their or a loved one’s condition. It is important for providers to be aware of such concerns and experiences. The goal of this study was to identify the primary concerns expressed on these discussion boards regarding Chiari malformation type I (CM) and to help guide clinicians in understanding patient challenges in the treatment of CM. METHODS The authors performed thematic analysis of anonymous online discussion board posts as identified through internet search engines. They then adopted a previously developed grounded theory method that utilizes a three-tiered coding and grouping process of posts based on commonly discovered content themes. RESULTS Analysis of 400 discussion board posts identified four distinct themes raised by CM patients and their caregivers: the path to diagnosis, symptoms experienced, surgical intervention, and high emotional burden. Although each individual experience was unique, the path toward a CM diagnosis was expressed as a journey involving multiple physicians, alternative diagnoses, and feelings of dismissal from providers. The most common reported symptoms included dizziness, headaches, neck and back pain, sensory issues, weakness and paresthesias of the extremities, speech issues, and general fatigue. Additionally, there was an overall sense of uncertainty from patients seeking advice regarding surgical intervention, with users expressing diverse sentiments that included both positive and negative outcomes regarding surgical treatment. Lastly, a wide range of emotions was expressed related to a CM diagnosis, including concern, worry, anxiety, depression, stress, fear, and frustration. CONCLUSIONS CM is a frequent imaging diagnosis identified in patients presenting with a wide range of symptoms, and as a result this leads to a diverse set of patient experiences. Analysis of CM patient and caregiver discussion boards revealed key themes that clinicians may address when counseling for CM. © 2024 American Association of Neurological Surgeons. All rights reserved.
Author Keywords
Chiari malformation; congenital; discussion boards; patient experience; thematic analysis
Document Type: Article
Publication Stage: Final
Source: Scopus
The response of Dual-leucine zipper kinase (DLK) to nocodazole: Evidence for a homeostatic cytoskeletal repair mechanism
(2024) PLoS ONE, 19 (4 April), art. no. e0300539, .
DeVault, L.a , Mateusiak, C.b c , Palucki, J.a , Brent, M.b c , Milbrandt, J.b d , DiAntonio, A.a d
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MI, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MI, United States
c Department of Computer Science & Engineering, Washington University, St. Louis, MO, United States
d Needleman Center for Neurometabolism and AxonalTherapeutics, Washington University School of Medicine, St. Louis, MI, United States
Abstract
Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that low dose nocodazole treatment activates DLK signaling. Activation of DLK signaling results in a DLK-dependent transcriptional signature, which we identify through RNAseq. This signature includes genes likely to attenuate DLK signaling while simultaneously inducing actin regulating genes. We identify alterations to the cytoskeleton including actinbased morphological changes to the axon. These results are consistent with the model that cytoskeletal disruption in the neuron induces a DLK-dependent homeostatic mechanism, which we term the Cytoskeletal Stress Response (CSR) pathway. © 2024 Public Library of Science. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Blood-Based Proteomics for Adult-Onset Focal Dystonias
(2024) Annals of Neurology, .
Timsina, J.a b , Dinasarapu, A.c , Kilic-Berkmen, G.c , Budde, J.a b , Sung, Y.J.a b d , Klein, A.M.e , Cruchaga, C.a b f , Jinnah, H.A.c g
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Otolaryngology, Emory University School of Medicine, Atlanta, GA, United States
f Hope Center for Neurologic Diseases, Washington University in St. Louis, St. Louis, MO, United States
g Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
Abstract
Objectives: The adult-onset focal dystonias are characterized by over-active muscles leading to abnormal movements. For most cases, the etiology and pathogenesis remain unknown. In the current study, unbiased proteomics methods were used to identify potential changes in blood plasma proteins. Methods: A large-scale unbiased proteomics screen was used to compare proteins (N = 6,345) in blood plasma of normal healthy controls (N = 49) with adult-onset focal dystonia (N = 143) consisting of specific subpopulations of cervical dystonia (N = 45), laryngeal dystonia (N = 49), and blepharospasm (N = 49). Pathway analyses were conducted to identify relevant biological pathways. Finally, protein changes were used to build a prediction model for dystonia. Results: After correction for multiple comparisons, 15 proteins were associated with adult-onset focal dystonia. Subgroup analyses revealed some proteins were shared across the dystonia subgroups while others were unique to 1 subgroup. The top biological pathways involved changes in the immune system, metal ion transport, and reactive oxygen species. A 4-protein model showed high accuracy in discriminating control individuals from dystonia cases [average area under the curve (AUC) = 0.89]. Interpretation: These studies provide novel insights into the etiopathogenesis of dystonia, as well as novel potential biomarkers. ANN NEUROL 2024. © 2024 American Neurological Association.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exploring the association between weight loss-inducing medications and multiple sclerosis: insights from the FDA adverse event reporting system database
(2024) Therapeutic Advances in Neurological Disorders, 17, .
Shirani, A.a , Cross, A.H.b , Stuve, O.c
a Department of Neurological Sciences, University of Nebraska Medical Center, Nebraska Medical Center, 988440, Omaha, NE 68198-8440, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Department of Neurology, University of Texas Southwestern Medical Center, Dallas VA Medical Center, Dallas, TX, United States
Abstract
Background: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities. Objective: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database. Design: Secondary analysis of existing data from the FAERS database. Methods: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1. Results: We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132–0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109–0.248), liraglutide (ROR: 0.161; 95% CI: 0.091–0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146–0.377), and metformin (ROR: 0.387; 95% CI: 0.340–0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384–0.806). Conclusion: Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies. © The Author(s), 2024.
Author Keywords
disproportionality analysis; FDA Adverse Event Reporting System database; glucagon-like peptide-1 receptor agonists; multiple sclerosis; weight loss-inducing drugs
Document Type: Article
Publication Stage: Final
Source: Scopus
A qualitative analysis of patient and caregiver experiences with myelomeningocele through online discussion boards
(2024) Child’s Nervous System, .
Koneru, S.a , Bhavsar, S.a , Pugazenthi, S.a , Koller, G.M.a , Karuparti, S.a , Kann, M.R.b , Strahle, J.M.a
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Abstract
Purpose: Patients and caregivers impacted by myelomeningocele (MMC) use online discussion board forums to create community and share information and concerns about this complex medical condition. We aim to identify the primary concerns expressed on these forums with the goal of understanding gaps in care that may merit investment of resources to improve care received by this population. Methods: Anonymous posts from online MMC discussion boards were compiled using internet search engines. Posts were then analyzed using an adaptation of the Grounded Theory Method, a three-step system involving open, axial, and selective coding of the data by two independent researchers to identify common themes. Results: Analysis of 400 posts written primarily by parents (n = 342, 85.5%) and patients (n = 45, 11.25%) yielded three overarching themes: questions surrounding quality of life, a lack of support for mothers of children with MMC, and confusion with a complex healthcare system. Many posts revealed concerns about management and well-being with MMC, including posts discussing symptoms and related conditions (n = 299, 75.75%), treatments (n = 259, 65.75%), and emotional aspects of MMC (n = 146, 36.5%). Additionally, families, especially mothers, felt a lack of support in their roles as caregivers. Finally, in 118 posts (29.5%), patients and families expressed frustration with navigating a complex healthcare system and finding specialists whose opinions they trusted. Conclusions: MMC is a complex medical condition that impacts patients and families in unique ways. Analysis of online discussion board posts identified key themes to be addressed in order to improve the healthcare experiences of those impacted by MMC. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
Author Keywords
Caregiver experience; Discussion boards; Myelomeningocele; Patient experience; Thematic analysis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus