👤 Jennifer C Kelley

Posttraumatic stress disorder (PTSD) has been associated with accelerated cognitive aging and increased risk for Alzheimer's disease (AD) and related dementias (ADRD), yet the neural substrates linking trauma-related psychiatric illness to late-life neurodegenerative vulnerability remain poorly defined. The amygdala plays a central role in threat processing and emotional memory and exhibits persistent hyperactivity in PTSD, but its molecular and pathological state in aging individuals with PTSD has not been systematically examined. Postmortem amygdala tissue from older adult donors (≥ 70 years) with lifetime PTSD (n = 5) and age-matched controls (n = 5) was obtained from the National PTSD Brain Bank. A multimodal analysis was performed integrating immunohistochemical quantification of β-amyloid and phosphorylated tau pathology, targeted transcriptional profiling of AD-related genes, gene network analysis, and protein quantification of pathological, inflammatory, and synaptic markers. PTSD cases showed enrichment of combined tau-amyloid pathology within the amygdala and significantly greater β-amyloid burden. Targeted transcriptomic profiling identified coordinated upregulation of AD-related genes involved in amyloid processing, lipid metabolism, proteostasis, and inflammatory signaling. Network analysis revealed an APP-centered molecular architecture with APOE, MAPT, and CLU functioning as highly connected secondary hubs. Protein analyses demonstrated increased amyloid-β and pTau231 abundance, selective markers of gliosis, and synaptic alterations characterized by elevated excitatory receptor expression and reduced inhibitory GABABR1a. Older adults with PTSD exhibit convergent evidence of AD-relevant molecular and pathological remodeling in the amygdala. These findings suggest that chronic trauma-related circuit dysregulation may intersect with aging-associated inflammatory and synaptic processes, creating a biological environment permissive for neurodegenerative vulnerability in emotionally salient brain circuits. Show less

Endometriosis has a significant impact on the social, psychological, psychosomatic, and physical aspects of women's lives. There is increasing evidence that endometriosis has to be seen as a systemic and complex disorder with a multifactorial etiology, accompanied by numerous other pathologies, such as mental disorders and even cancer. Herein, we analyzed Disability-Adjusted Life Years (DALYs) and Years Lived with Disability (YLDs) generated from the Global Burden of Disease Study (GBD 2021), which are key metrics used to measure the worldwide impact of diseases. Besides, differential gene expression data generated from the Turku Endomet Database were calculated. Briefly, log2-transformed gene expression counts were investigated using linear modeling with the function expression ~ condition to generate log2 fold changes and Show less

Transcription must be tightly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains rudimentary. Here, by dissecting the function of the SET1 chromatin-modifying complexes that bind to CpG island-associated gene promoters, we discover that they play a specific and essential role in enabling the expression of low to moderately transcribed genes. Counterintuitively, this effect can occur independently of SET1 complex histone-modifying activity and instead relies on an interaction with the RNA Polymerase II-binding protein WDR82. Unexpectedly, we discover that SET1 complexes enable gene expression by antagonising premature transcription termination by the ZC3H4/WDR82 complex at CpG island-associated genes. In contrast, at extragenic sites of transcription, which typically lack CpG islands and SET1 complex occupancy, we show that the activity of ZC3H4/WDR82 is unopposed. Therefore, we reveal a gene regulatory mechanism whereby CpG islands are bound by a protein complex that specifically protects genic transcripts from premature termination, effectively distinguishing genic from extragenic transcription and enabling normal gene expression. Show less

Chronic inflammatory pain represents one of the largest subsets of chronic pain diagnoses, which affect nearly a quarter of individuals in the United States and cost nearly $600 billion dollars annually. Chronic pain leads to persistent sensory hypersensitivities, as well as emotional and cognitive disturbances. Evidence suggests that melanocortin 4 receptors (MC4Rs) mediate pain-signaling and pain-like behaviors via actions at various nodes in the pain-neural axis, but the field lacks a complete understanding of the potential role of MC4Rs in chronic inflammatory pain in males and females. The central amygdala (CeA) expresses high quantities of MC4R and receives pain-related information from the periphery, and in vivo CeA manipulations alter nociceptive behavior in pain-naïve and in animals with chronic pain. Here, we tested the hypothesis that MC4Rs in the CeA modulate thermal nociception and mechanical sensitivity, as well as pain avoidance, in male and female Wistar rats, using a model of chronic inflammatory pain (Complete Freud's Adjuvant; CFA). First, we report that CFA produces long-lasting hyperalgesia in adult male and female Wistar rats, and long-lasting pain avoidance in male Wistar rats. Second, we report that MC4R antagonism in the CeA reduces thermal nociception and mechanical sensitivity in male and female Wistar rats treated with CFA. Finally, we report that MC4R antagonism in the CeA reduces pain avoidance in male, and that this effect is not due to drug effects on locomotor activity. Our results indicate that a model of chronic inflammatory pain produces long-lasting increases in pain-like behaviors in adult male and female Wistar rats, and that antagonism of MC4Rs in the CeA reverses those effects. Show less

We report a case of severe type I hyperlipoproteinemia caused by autoimmunity against lipoprotein lipase (LPL) in the context of presymptomatic Sjögren's syndrome. A 7-year-old mixed race (Caucasian/African American) girl was admitted to the intensive care unit at Vanderbilt Children's Hospital with acute pancreatitis and shock. She was previously healthy aside from asthma and history of Hashimoto's thyroiditis. Admission triglycerides (TGs) were 2191 mg/dL but returned to normal during the hospital stay and in the absence of food intake. At discharge, she was placed on a low-fat, low-sugar diet. She did not respond to fibrates, prescription fish oil, metformin, or orlistat, and during the following 2 years, she was hospitalized several times with recurrent pancreatitis. Except for a heterozygous mutation in the promoter region of LPL, predicted to have no clinical significance, she had no further mutations in genes known to affect TG metabolism and to cause inherited type I hyperlipoproteinemia, such as APOA5, APOC2, GPIHBP1, or LMF1. When her TG levels normalized after incidental use of prednisone, an autoimmune mechanism was suspected. Immunoblot analyses showed the presence of autoantibodies to LPL in the patient's plasma. Autoantibodies to LPL decreased by 37% while patient was on prednisone, and by 68% as she subsequently transitioned to hydroxychloroquine monotherapy. While on hydroxychloroquine, she underwent a supervised high-fat meal challenge and showed normal ability to metabolize TG. For the past 3 years and 6 months, she has had TG consistently <250 mg/dL, and no symptoms of, or readmissions for, pancreatitis. Show less

Mouse CA1 pyramidal neurons express apamin-sensitive SK2-containing channels in the post-synaptic membrane, positioned close to NMDA-type (N-methyl-D-aspartate) glutamate receptors. Activated by synaptically evoked NMDAR-dependent Ca(2+) influx, the synaptic SK2-containing channels modulate excitatory post-synaptic responses and the induction of synaptic plasticity. In addition, their activity- and protein kinase A-dependent trafficking contributes to expression of long-term potentiation (LTP). We have identified a novel synaptic scaffold, MPP2 (membrane palmitoylated protein 2; p55), a member of the membrane-associated guanylate kinase (MAGUK) family that interacts with SK2-containing channels. MPP2 and SK2 co-immunopurified from mouse brain, and co-immunoprecipitated when they were co-expressed in HEK293 cells. MPP2 is highly expressed in the post-synaptic density of dendritic spines on CA1 pyramidal neurons. Knocking down MPP2 expression selectively abolished the SK2-containing channel contribution to synaptic responses and decreased LTP. Thus, MPP2 is a novel synaptic scaffold that is required for proper synaptic localization and function of SK2-containing channels. Show less

Microtubule actin crosslinking factor 1 (MACF1) plays a role in the coordination of microtubules and actin in multiple cellular processes. Here, we show that MACF1 is also critical for ciliogenesis in multiple cell types. Ablation of Macf1 in the developing retina abolishes ciliogenesis, and basal bodies fail to dock to ciliary vesicles or migrate apically. Photoreceptor polarity is randomized, while inner retinal cells laminate correctly, suggesting that photoreceptor maturation is guided by polarity cues provided by cilia. Deletion of MACF1 in adult photoreceptors causes reversal of basal body docking and loss of outer segments, reflecting a continuous requirement for MACF1 function. MACF1 also interacts with the ciliary proteins MKKS and TALPID3. We propose that a disruption of trafficking across microtubles to actin filaments underlies the ciliogenesis defect in cells lacking MACF1 and that MKKS and TALPID3 are involved in the coordination of microtubule and actin interactions. Show less

Depression symptoms following immune response to a challenge have been reported after the recovery from sickness. A RNA-Seq study of the dysregulation of the microglia transcriptome in a model of inflammation-associated depressive behavior was undertaken. The transcriptome of microglia from mice at day 7 after Bacille Calmette Guérin (BCG) challenge was compared to that from unchallenged Control mice and to the transcriptome from peripheral macrophages from the same mice. Among the 562 and 3,851 genes differentially expressed between BCG-challenged and Control mice in microglia and macrophages respectively, 353 genes overlapped between these cells types. Among the most differentially expressed genes in the microglia, serum amyloid A3 (Saa3) and cell adhesion molecule 3 (Cadm3) were over-expressed and coiled-coil domain containing 162 (Ccdc162) and titin-cap (Tcap) were under-expressed in BCG-challenged relative to Control. Many of the differentially expressed genes between BCG-challenged and Control mice were associated with neurological disorders encompassing depression symptoms. Across cell types, S100 calcium binding protein A9 (S100A9), interleukin 1 beta (Il1b) and kynurenine 3-monooxygenase (Kmo) were differentially expressed between challenged and control mice. Immune response, chemotaxis, and chemokine activity were among the functional categories enriched by the differentially expressed genes. Functional categories enriched among the 9,117 genes differentially expressed between cell types included leukocyte regulation and activation, chemokine and cytokine activities, MAP kinase activity, and apoptosis. More than 200 genes exhibited alternative splicing events between cell types including WNK lysine deficient protein kinase 1 (Wnk1) and microtubule-actin crosslinking factor 1(Macf1). Network visualization revealed the capability of microglia to exhibit transcriptome dysregulation in response to immune challenge still after resolution of sickness symptoms, albeit lower than that observed in macrophages. The persistent transcriptome dysregulation in the microglia shared patterns with neurological disorders indicating that the associated persistent depressive symptoms share a common transcriptome basis. Show less

Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase–like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and β(LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined. Show less