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Palmitoylation is the post-translational addition of the 16-carbon fatty acid palmitate to protein cysteine residues. This process is best known for its roles in targeting proteins to lipid membranes, including both the plasma membrane and vesicles. Palmitoylation occurs in all eukaryotic cells, but appears to be particularly important in neurons, because genetic mutation or loss of several palmitoyl acyltransferases (PATs, the enzymes that catalyze palmitoylation), leads to predominantly neuropathological defects. In addition, a growing number of recent studies have revealed key roles for palmitoylation of specific proteins in neuronal regulation. However, most of these studies have focused on how palmitoylation regulates postsynaptic protein targeting. In contrast, it is far less clear how palmitoylation might regulate the specialized subcellular processes that are important in axons. One particularly important process in axons is retrograde signaling, in which information is conveyed from distal locations back to the cell body. Following injury to axons of the peripheral nervous system (PNS), retrograde signals are critical to activate transcription of pro-regenerative genes. Key retrograde signaling pathways include the DLK/JNK/c-Jun (Dual Leucine Zipper Kinase/c-Jun N-terminal Kinase/c-Jun) signaling pathway and the GP130/JAK/STAT (Glycoprotein 130/Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway, both of which are activated following nerve injury and are vital to promote regeneration. Though both of these pathways are critical for conveying distal information from the periphery to the cell body, many of their component proteins are predicted to be soluble and diffusible. This raises the question of how these proteins can directionally signal over the long distances that axons extend. Interestingly, bio-informatic and proteomic studies suggested that DLK, GP130, JAK and STAT may be palmitoylated. We hypothesized that palmitoylation could be important for the roles of these proteins in retrograde signaling. Because retrograde signals are initiated in distal axons, a considerable distance from the cell body, we further hypothesized axonally localized PATs might play key roles in the control of retrograde signaling. We find that the retrograde signaling protein DLK is palmitoylated at a highly conserved cysteine residue. This modification is necessary for its localization to motile vesicles and for its interaction with the retrograde signaling protein JIP3. Notably, we also describe a novel role for palmitoylation in regulating DLK’s kinase activity. In addition, our study identifies the first axonally enriched PATs in sensory neurons; DHHC5 and DHHC8. shRNA knockdown experiments in sensory neurons reveal that these axonal PATs control both palmitoylation and surface expression of GP130 and are essential for GP130/JAK/STAT3-dependent retrograde signaling. These findings reveal a novel role for palmitoylation in the control of axonal retrograde signaling, provide key insights into the molecular roles of this modification and identify new potential targets for therapy to improve nerve regeneration post-injury. / Biomedical Sciences

Combination antiretroviral therapy (cART)-treated people living with human immunodeficiency virus (HIV) (PLWH) face an increased risk of atherosclerosis associated cardiovascular disease (ASCVD) even after controlling for traditional and non-traditional risk factors (Freiberg et al. 2013). Persistent HIV-associated immune activation (monocyte and T-cell activation) is believed to contribute to heightened complications of ASCVD including, myocardial infarction (MI), and stroke in PLWH (Hsue et al. 2009; Kearns et al. 2017). Specifically, systemic immune activation predisposes PLWH to arterial inflammation (characterized by increased arterial macrophage infiltration), and accelerated atherogenesis (Lo et al. 2010; Burdo, Lo, et al. 2011; Fitch et al. 2013; Subramanian et al. 2012; Tawakol et al. 2016). Accelerated atherogenesis has even been noted among elite controllers, or PLWH who maintain undetectable virus levels in the absence of cART (Pereyra et al. 2012), suggesting that the proc / Biomedical Sciences

JC virus (JCV) is a human neurotropic polyomavirus and the etiologic agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the white matter. PML is primarily observed in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS) and those prescribed immunomodulatory therapies. During JCV infection, the virus encodes multiple viral proteins including T-antigen and agnoprotein. Originally, we demonstrated that T-antigen expression rescued serine/arginine rich splicing factor 1 (SRSF1)-mediated transcriptional suppression of JCV for both early and late promoter orientations. We demonstrated that T-antigen expression suppressed SRSF1 expression in glial cells through inhibition of SRSF1 transcription. We have recently shown that agnoprotein is secreted from transfected cells into the extracellular matrix, where it is internalized by neighboring uninfected astrocytes or microglia. The internalization of agnoprotein was found to impact astrocyte’s cytokine profile, with treatment of astrocytes with media containing agnoprotein resulting in a significant reduction in granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Subsequent reporter gene analysis demonstrated that agnoprotein can suppress GM-CSF transcription, implicating a possible mechanism for the reduction of GM-CSF secretion. Likewise, the treatment of a human monocyte cell line, U-937, with agnoprotein resulted in decreased differentiation, dysregulated surface marker expression, and decreased phagocytic ability. Similarly, treatment of peripheral blood mononuclear cells with agnoprotein decreased cellular migration through an in vitro blood brain barrier model. These findings have suggested that extracellular agnoprotein modulates aspects of the immune response to JCV, primarily through suppression of GM-CSF secretion and a subsequent dysregulation on monocyte/macrophage function. / Infectious Disease & Immunity

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting over five million people in the US alone. Causes for the most common sporadic form of the disease are still obscure and no therapeutic approach is available to halt the progression of AD. Subjects whose mothers were affected by sporadic AD are three times more susceptible to develop the disease later in life compared to subject from sporadic AD fathers. However, the mechanisms of maternal transmissibility for sporadic AD are unknown. Lifestyle and nutrition are important risk factors for sporadic AD. Direct exposure to saturated fats and cholesterol is positively correlated to AD development later in life. We hypothesized that maternal exposure to high-fat diet throughout gestation would affect AD susceptibility in the offspring later in life. To tackle this biological question, triple transgenic (3xTg) dams carrying human APP (KM670/671NL), PSEN1 (M146V) and MAPT (P301L) mutations together with wild type da / Biomedical Sciences

Alcohol consumption leads to a number of disorders most notably ALD, alcoholism, and inflammation. The present study aimed to investigate the effects of a Lieber-DeCarli chronic-plus-single-binge alcohol model on animal withdrawal behaviors to 1) to determine if this model manifests any symptoms of withdrawal and 2) how severely the symptoms are expressed. To evaluate alcohol’s effect(s), a variety of behavioral assays were performed, and several of the tests exhibited signs of increased withdrawal-like behavior in ethanol exposed mice, most notably showing anxiety and convulsion-like behaviors. Inflammation is one of the main hallmarks of alcohol associated diseases and pathologies. Two of the main organs affected by alcohol induced inflammation are the brain and the liver; both of which have been shown to be structurally and physiologically disturbed by chronic alcohol consumption. Two compounds from the cannabis plant, cannabidiol and beta-caryophyllene have been isolated and shown to have anti- inflammatory properties. The potential anti-inflammatory effects of both compounds separately and in combination were assessed against ethanol exposure using a chronic- plus-single-binge alcohol model using a Lieber-DeCarli liquid diet. Immunofluorescence analysis of brain microglia and liver Kupffer cells was used to evaluate the inflammatory profile affected by alcohol and by treatment with cannabinoids. A second cohort of mice exposed to ethanol and administered CBD, BCP or both cannabinoids together was used to investigate if these compounds had effects on inflammatory cytokine concentrations or accumulation of fat in the liver. Luminex assays were used for analysis of specific cytokines in the serum and oil red o staining was used to see the potential effect on fat accumulation. Spinal cord injury results in a massive secondary inflammatory reaction that can compound on the already physically damaged tissue. Ethanol is known to induce inflammation when consumed acutely and chronically. To assess the effect of ethanol consumption on spinal cord injury we investigate pain sensitivity, motor and sensory recovery as well as the size of the lesion at the site of impact on the spinal cord. To examine motor recovery, we use a Basso Mouse Scale (BMS) for locomotion which assesses the mouse’s ability to move various parts of their hind limbs and overall coordination. Lesion size is measured using a previously characterized eriochrome cyanine with cresyl violet counterstain that elucidates damaged areas of the spinal cord in both the white and gray matter. Additionally, the glial profile was observed and quantified using a GFAP immunofluorescence stain. Interestingly, mice given ethanol had improved BMS scores when compared to control diet counterparts. Furthermore, lesion size and glial profile were also reduced in ethanol animals, showing that ethanol can have a protective, immune-suppressive effect when consumed after injury, thereby limiting secondary insult that results from SCI. / Neuroscience