MSTPublications: June 2020
DEPDC5 haploinsufficiency drives increased mTORC1 signaling and abnormal morphology in human iPSC-derived cortical neurons.
Klofas LK, Short BP, Snow JP, Sinnaeve J, Rushing GV, Westlake G, Weinstein W, Ihrie RA, Ess KC, Carson RP.
Neurobiol Dis. 2020 Jun 20:104975. doi: 10.1016/j.nbd.2020.104975. [Epub ahead of print]
Mutations in the DEPDC5 gene can cause epilepsy, including forms with and without brain malformations. The goal of this study was to investigate the contribution of DEPDC5 gene dosage to the underlying neuropathology of DEPDC5-related epilepsies. We generated induced pluripotent stem cells (iPSCs) from epilepsy patients harboring heterozygous loss of function mutations in DEPDC5. Patient iPSCs displayed increases in both phosphorylation of ribosomal protein S6 and proliferation rate, consistent with elevated mTORC1 activation. In line with these findings, we observed increased soma size in patient iPSC-derived cortical neurons that was rescued with rapamycin treatment. These data indicate that human cells heterozygous for DEPDC5 loss-of-function mutations are haploinsufficient for control of mTORC1 signaling. Our findings suggest that human pathology differs from mouse models of DEPDC5-related epilepsies, which do not show consistent phenotypic differences in heterozygous neurons, and support the need for human-based models to affirm and augment the findings from animal models of DEPDC5-related epilepsy.
High-throughput discovery of trafficking-deficient variants in the cardiac potassium channel KV11.1.
Kozek KA, Glazer AM, Ng CA, Blackwell D, Egly CL, Vanags LR, Blair M, Mitchell D, Matreyek KA, Fowler DM, Knollmann BC, Vandenberg JI, Roden DM, Kroncke BM.
Heart Rhythm. 2020 Jun 6. pii: S1547-5271(20)30542-7. doi: 10.1016/j.hrthm.2020.05.041. [Epub ahead of print]
Background: KCHN2 encodes the KV11.1 potassium channel responsible for IKr, a major repolarization current during the cardiomyocyte action potential. Variants in KCNH2 that lead to decreased IKr have been associated with Type 2 Long QT syndrome (LQT2). The mechanism of LQT2 is most often induced loss of KV11.1 trafficking to the cell surface. Accurately discriminating between variants with normal and abnormal trafficking would aid in understanding the deleterious nature of these variants; however, the volume of reported nonsynonymous KCNH2 variants precludes the use of conventional methods for functional study.
Objective: We report a high-throughput, multiplexed screening method for KCNH2 genetic variants capable of measuring the cell surface abundance of hundreds of missense variants in the resulting KV11.1 channel.
Methods: We developed a method to quantitate KV11.1 variant trafficking on a pilot region of 11 residues in the S5 helix.
Results: We generated trafficking scores for 220/231 missense variants in the pilot region. For 5/5 variants, high-throughput trafficking scores validated when tested in single variant flow cytometry and confocal microscopy experiments. We further explored these results with planar patch electrophysiology and found that loss-of-trafficking variants indeed do not produce IKr. Conversely, but expectedly, some variants that traffic normally were still functionally compromised.
Conclusions: Here, we described a new method for detecting KV11.1 trafficking-deficient variants in a multiplexed assay. This new method accurately generated trafficking data for variants in KV11.1 and is extendable both to all residues in Kv11.1 and to other cell surface proteins.
Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences.
Moore EE, Liu D, Pechman KR, Acosta LMY, Bell SP, Davis LT, Blennow K, Zetterberg H, Landman BA, Schrag MS, Hohman TJ, Gifford KA, Jefferson AL.
Front Aging Neurosci. 2020 Jun 5;12:139. doi: 10.3389/fnagi.2020.00139. eCollection 2020.
Introduction: While Alzheimer’s disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages.
Methods: Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models.
Results: Stages differed at baseline on APOE-ε4 status (early < middle = late; p-values < 0.03) and CSF Aβ (early > middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03).
Discussion: Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets.
Selective enhancement of object representations through multisensory integration.
Tovar DA, Murray MM, Wallace MT.
J Neurosci. 2020 Jun 4. pii: JN-RM-2139-19. doi: 10.1523/JNEUROSCI.2139-19.2020. [Epub ahead of print]
Objects are the fundamental building blocks of how we create a representation of the external world. One major distinction amongst objects is between those that are animate versus inanimate. In addition, many objects are specified by more than a single sense, yet the nature by which multisensory objects are represented by the brain remains poorly understood. Using representational similarity analysis of male and female human EEG signals, we show enhanced encoding of audiovisual objects when compared to their corresponding visual and auditory objects. Surprisingly, we discovered that the often-found processing advantages for animate objects was not evident under multisensory conditions. This was due to a greater neural enhancement of inanimate objects-which are more weakly encoded under unisensory conditions. Further analysis showed that the selective enhancement of inanimate audiovisual objects corresponded with an increase in shared representations across brain areas, suggesting that the enhancement was mediated by multisensory integration. Moreover, a distance-to-bound analysis provided critical links between neural findings and behavior. Improvements in neural decoding at the individual exemplar level for audiovisual inanimate objects predicted reaction time differences between multisensory and unisensory presentations during a go/no-go animate categorization task. Links between neural activity and behavioral measures were most evident at intervals 100-200ms and 350-500ms after stimulus presentation, corresponding to time periods associated with sensory evidence accumulation and decision-making, respectively. Collectively, these findings provide key insights into a fundamental process the brain uses to maximize information it captures across sensory systems to perform object recognition.
Significance Statement: Our world is filled with ever-changing sensory information that we are able to seamlessly transform into a coherent and meaningful perceptual experience. We accomplish this feat by combining different stimulus features into objects. However, despite the fact that these features span multiple senses, little is known about how the brain combines the various forms of sensory information into object representations. Here, we used EEG and machine learning to study how the brain processes auditory, visual, and audiovisual objects. Surprisingly, we found that non-living (i.e., inanimate) objects, which are more difficult to process with one sense alone, benefited the most from engaging multiple senses.
Cross-reactivity between vancomycin, teicoplanin and telavancin in HLA-A*32:01 positive vancomycin DRESS patients sharing an HLA-Class II haplotype.
Nakkam N, Gibson A, Mouhtouris E, Konvinse K, Holmes N, Chua KY, Deshpande P, Li D, Ostrov DA, Trubiano J, Phillips EJ.
J Allergy Clin Immunol. 2020 May 18. pii: S0091-6749(20)30687-4. doi: 10.1016/j.jaci.2020.04.056. [Epub ahead of print]
Data highlighting phenotypic diversity of urine-associated Escherichia coli isolates.
Eberly AR, Beebout CJ, Tong CMC, Van Horn GT, Green HD, Fitzgerald MJ, De S, Apple EK, Schrimpe-Rutledge AC, Codreanu SG, Sherrod SD, McLean JA, Clayton DB, Stratton CW, Schmitz JE, Hadjifrangiskou M.
Data Brief. 2020 Jun 3;31:105811. doi: 10.1016/j.dib.2020.105811. eCollection 2020 Aug.
Invasion of vaginal epithelial cells by uropathogenic Escherichia coli.
Brannon JR, Dunigan TL, Beebout CJ, Ross T, Wiebe MA, Reynolds WS, Hadjifrangiskou M.
Nat Commun. 2020 Jun 4;11(1):2803. doi: 10.1038/s41467-020-16627-5.
Pharmacological readthrough of R294X Mecp2 in a novel mouse model of Rett Syndrome.
Merritt JK, Collins BE, Erickson KR, Dong H, Neul JL.
Hum Mol Genet. 2020 May 29. pii: ddaa102. doi: 10.1093/hmg/ddaa102. [Epub ahead of print]
MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy.
Jiang X, Dudzinski S, Beckermann KE, Young K, McKinley E, J McIntyre O, Rathmell JC, Xu J, Gore JC.
J Immunother Cancer. 2020 Jun;8(1). pii: e000328. doi: 10.1136/jitc-2019-000328.
Association between supratentorial pediatric high-grade gliomas involved with the subventricular zone and decreased survival: a multi-institutional retrospective study.
Mistry AM, Mummareddy N, CreveCoeur TS, Lillard JC, Vaughn BN, Gallant JN, Hale AT, Griffin N, Wellons JC, Limbrick DD, Klimo P, Naftel RP.
J Neurosurg Pediatr. 2020 May 22:1-7. doi: 10.3171/2020.3.PEDS19593.
Thalamic arousal network disturbances in temporal lobe epilepsy and improvement after surgery.
González HFJ, Chakravorti S, Goodale SE, Gupta K, Claassen DO, Dawant B, Morgan VL, Englot DJ.
J Neurol Neurosurg Psychiatry. 2019 Oct;90(10):1109-1116. doi: 10.1136/jnnp-2019-320748. Epub 2019 May 23. Erratum in: Neurosurgery. 2020 Feb 1;86(2):315.
Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline.
Archer DB, Moore EE, Shashikumar N, Dumitrescu L, Pechman KR, Landman BA, Gifford KA, Jefferson AL, Hohman TJ.
Neurobiol Aging. 2020 May 12;94:15-23. doi: 10.1016/j.neurobiolaging.2020.05.001. [Epub ahead of print]
Prehospital plasma in injured patients is associated with survival principally in blunt injury: Results from two randomized prehospital plasma trials.
Reitz KM, Moore HB, Guyette FX, Sauaia A, Pusateri AE, Moore EE, Hassoune A, Chapman MP, Daley BJ, Miller RS, Harbrecht BG, Claridge JA, Phelan HA, Brown JB, Zuckerbraun BS, Neal MD, Yazer MH, Sperry JL.
J Trauma Acute Care Surg. 2020 Jan;88(1):33-41. doi: 10.1097/TA.0000000000002485.
High-Throughput Reclassification of SCN5A Variants.
Glazer AM, Wada Y, Li B, Muhammad A, Kalash OR, O’Neill MJ, Shields T, Hall L, Short L, Blair MA, Kroncke BM, Capra JA, Roden DM.
Am J Hum Genet. 2020 Jun 5. pii: S0002-9297(20)30162-2. doi: 10.1016/j.ajhg.2020.05.015. [Epub ahead of print]
The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma.
McBride MA, Owen AM, Stothers CL, Hernandez A, Luan L, Burelbach KR, Patil TK, Bohannon JK, Sherwood ER, Patil NK.
Front Immunol. 2020 May 29;11:1043. doi: 10.3389/fimmu.2020.01043. eCollection 2020. Review.