Contributions of VPS35 Mutations to Parkinson’s Disease

Parkinson’s Disease (PD) is a multi-system neurodegenerative disease where approximately 90% of cases are idiopathic. The remaining 10% of the cases can be traced to a genetic origin and research has largely focused on these associated genes to gain a better understanding of the molecular and cellular pathogenesis for PD. The gene encoding vacuolar protein sorting protein 35 (VPS35) has been definitively linked to late onset familial PD following the identification of a point mutation (D620N) as the causal agent in a Swiss family. Since its discovery, numerous studies have been undertaken to characterize the role of VPS35 in cellular processes and efforts have been directed toward understanding the perturbations caused by the D620N mutation. In this review, we examine what is currently known about VPS35, which has pleiotropic effects, as well as proposed mechanisms of pathogenesis by the D620N mutation. A brief survey of other VPS35 polymorphisms is also provided. Lastly, model systems that are being utilized for these investigations and possible directions for future research are discussed

Signaling and Other Functions of Lipids in Autophagy: A Review

The process of autophagy is integral to cellular function. In this process, proteins, organelles, and metabolites are engulfed in a lipid vesicle and trafficked to a lysosome for degradation. Its central role in protein and organelle homeostasis has piqued interest for autophagy dysfunction as a driver of pathology for a number of diseases including cancer, muscular disorders, neurological disorders, and non-alcoholic fatty liver disease. For much of its history, the study of autophagy has centered around proteins, however, due to advances in mass spectrometry and refined methodologies, the role of lipids in this essential cellular process has become more apparent. This review discusses the diverse endogenous lipid compounds shown to mediate autophagy. Downstream lipid signaling pathways are also reviewed in the context of autophagy regulation. Specific focus is placed upon the Mammalian Target of Rapamycin (mTOR) and Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathways as integration hubs for lipid regulation of autophagy

Rescue of Lipid-Induced Autophagy Inhibition by Torin1 Treatment

Autophagy is an essential cellular process that degrades proteins and organelles and autophagy dysfunction is a hallmark of Parkinson’s disease and Alzheimer’s disease. Therefore, understanding how autophagy is regulated by lipid signaling factors can potentially reveal therapeutic targets for these diseases. Our lab has identified 3 lipids (5-oxo-ete, stearic acid and hydroxystearic acid) that repress autophagy using a lipidomic mass spectrometry screen of serum. RNA sequencing data suggests that mTOR might be affected by these lipids. We have therefore hypothesized that the 3 lipids inhibit autophagy by activating mTOR. To determine if these 3 lipids utilize mTOR for autophagy repression, we will treat differentiated human SH-SY5Y cells (neuron-like cells) with each lipid in the presence or absence of the mTOR inhibitor, Torin 1. Autophagy will then be assessed through examination of LC3-II protein levels by western blot. Our results will add to our understanding of the molecular mechanism of action for these 3 autophagy-repressing lipids which could ultimately aid in the development of treatments for neurodegenerative disease

Endothelial Cell Contributions to COVID-19

Understanding of the clinical, histological and molecular features of the novel coronavirus 2019 (Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)) has remained elusive. Coronavirus disease 2019 (COVID-19) caused by this virus has unusual clinical presentation with regard to other related coronaviruses. Recent reports suggest that SARS-CoV-2, unlike other related viruses, infects and replicates within endothelial cells, which may explain a significant portion of the observed clinical pathology. Likewise, mounting evidence associates vascular and endothelial cell dysfunction with increased mortality. This review focuses on understanding how endothelial cell pathology is caused by SARS-CoV-2 at the molecular and cellular levels and how these events relate to COVID-19. A detailed examination of current knowledge regarding canonical inflammatory reaction pathways as well as alteration of endothelial cell-derived exosomes and transdifferentiation by SARS-CoV-2 is included in this assessment. Additionally, given an understanding of endothelial contributions to COVID-19, potential therapeutic aims are discussed, particularly as would affect endothelial function and pathology

Nestin-Positive/SOX2−Negative Cells Mediate Adult Neurogenesis of Nigral Dopaminergic Neurons in Mice

The primary clinical motor symptoms of Parkinson’s disease (PD) result from loss of dopaminergic (DA) neurons in the substantia nigra (SN). Consequently, neurogenesis of this group of neurons in the adult brain has drawn considerable interest for the purpose of harnessing endogenous neurogenerative potential as well as devising better strategies for stem cell therapy for PD. However, the existence of adult neurogenesis for DA neurons within the SN remains controversial. To overcome technical and design limitations associated with previous studies, our group has developed a novel genetic mouse model for assessing adult nigral DA neurogenesis. This system utilizes transgenic mice that express a tamoxifen-activatable Cre recombinase (CreERT2) under the control of the neuronal progenitor cell promoters nestin or Sox2 leading to suppression of the DA neuron marker tyrosine hydroxylase (TH) via excision of exon 1 by flanking loxP sites in adult animals. This study reports that six months following initiation of a six week treatment with tamoxifen mice with nestin-mediated Th excision displayed a significant reduction in TH+ neurons in the SN. This finding indicates that nestin-expressing cells regenerate DA neurons within the SN of adult animals. Interestingly, no reduction was observed in TH+ cells following Sox2-mediated Th excision suggesting that a nestin+/SOX2‒ precursor cell population drives DA neurogenesis in the adult SN. This information represents a substantial leap in current knowledge of adult DA neurogenesis, will enable improved in vitro and in vivo modeling, as well as facilitate the harnessing of this process for therapeutic intervention for PD

The Role of NAD\u3csup\u3e+\u3c/sup\u3e and NAD\u3csup\u3e+\u3c/sup\u3e-Boosting Therapies in Inflammatory Response by IL-13

The essential role of nicotinamide adenine dinucleotide+ (NAD+) in redox reactions during oxidative respiration is well known, yet the coenzyme and regulator functions of NAD+ in diverse and important processes are still being discovered. Maintaining NAD+ levels through diet is essential for health. In fact, the United States requires supplementation of the NAD+ precursor niacin into the food chain for these reasons. A large body of research also indicates that elevating NAD+ levels is beneficial for numerous conditions, including cancer, cardiovascular health, inflammatory response, and longevity. Consequently, strategies have been created to elevate NAD+ levels through dietary supplementation with NAD+ precursor compounds. This paper explores current research regarding these therapeutic compounds. It then focuses on the NAD+ regulation of IL-13 signaling, which is a research area garnering little attention. IL-13 is a critical regulator of allergic response and is associated with Parkinson’s disease and cancer. Evidence supporting the notion that increasing NAD+ levels might reduce IL-13 signal-induced inflammatory response is presented. The assessment is concluded with an examination of reports involving popular precursor compounds that boost NAD+ and their associations with IL-13 signaling in the context of offering a means for safely and effectively reducing inflammatory response by IL-13

Creation and Curation of the Society of Imaging Informatics in Medicine Hackathon Dataset

In order to support innovation, the Society of Imaging Informatics in Medicine (SIIM) elected to create a collaborative computing experience called a "hackathon." The SIIM Hackathon has always consisted of two components, the event itself and the infrastructure and resources provided to the participants. In 2014, SIIM provided a collection of servers to participants during the annual meeting. After initial server setup, it was clear that clinical and imaging "test" data were also needed in order to create useful applications. We outline the goals, thought process, and execution behind the creation and maintenance of the clinical and imaging data used to create DICOM and FHIR Hackathon resources

Examining the effect of peer helping in a coping skills intervention: a randomized controlled trial for advanced gastrointestinal cancer patients and their family caregivers

PURPOSE: At the end of life, spiritual well-being is a central aspect of quality of life for many patients and their family caregivers. A prevalent spiritual value in advanced cancer patients is the need to actively give. To address this need, the current randomized trial examined whether adding a peer helping component to a coping skills intervention leads to improved meaning in life and peace for advanced gastrointestinal cancer patients and their caregivers. Feasibility and acceptability outcomes were also assessed. METHODS: Advanced gastrointestinal cancer patients and caregivers (n = 50 dyads) were randomly assigned to a 5-session, telephone-based coping skills intervention or a peer helping + coping skills intervention. One or both dyad members had moderate-severe distress. Peer helping involved contributing to handouts on coping skills for other families coping with cancer. Patients and caregivers completed measures of meaning in life/peace, fatigue, psychological symptoms, coping self-efficacy, and emotional support. Patient pain and caregiver burden were also assessed. RESULTS: Small effects in favor of the coping skills group were found regarding meaning in life/peace at 1 and 5 weeks post-intervention. Other outcomes did not vary as a function of group assignment, with both groups showing small decreases in patient and caregiver fatigue and caregiver distress and burden. High recruitment and retention rates supported feasibility, and high participant satisfaction ratings supported acceptability. CONCLUSIONS: Although a telephone-based intervention is feasible and acceptable for this population, peer helping in the context of a coping skills intervention does not enhance spiritual well-being relative to coping skills alone

The Masses of Population II White Dwarfs

Globular star clusters are among the first stellar populations to have formed in the Milky Way, and thus only a small sliver of their initial spectrum of stellar types are still burning hydrogen on the main-sequence today. Almost all of the stars born with more mass than 0.8 M_sun have evolved to form the white dwarf cooling sequence of these systems, and the distribution and properties of these remnants uniquely holds clues related to the nature of the now evolved progenitor stars. With ultra-deep HST imaging observations, rich white dwarf populations of four nearby Milky Way globular clusters have recently been uncovered, and are found to extend an impressive 5 - 8 magnitudes in the faint-blue region of the H-R diagram. In this paper, we characterize the properties of these population II remnants by presenting the first direct mass measurements of individual white dwarfs near the tip of the cooling sequence in the nearest of the Milky Way globulars, M4. Based on Gemini/GMOS and Keck/LRIS multiobject spectroscopic observations, our results indicate that 0.8 M_sun population II main-sequence stars evolving today form 0.53 +/- 0.01 M_sun white dwarfs. We discuss the implications of this result as it relates to our understanding of stellar structure and evolution of population II stars and for the age of the Galactic halo, as measured with white dwarf cooling theory.Comment: Accepted for Publication in Astrophys. J. on Aug. 05th, 2009. 19 pages including 9 figures and 2 tables (journal format

14-3-3 Proteins Interact with a Hybrid Prenyl-Phosphorylation Motif to Inhibit G Proteins

Signaling through G proteins normally involves conformational switching between GTP- and GDP-bound states. Several Rho GTPases are also regulated by RhoGDI binding and sequestering in the cytosol. Rnd proteins are atypical constitutively GTP-bound Rho proteins, whose regulation remains elusive. Here, we report a high-affinity 14-3-3-binding site at the C terminus of Rnd3 consisting of both the Cys241-farnesyl moiety and a Rho-associated coiled coil containing protein kinase (ROCK)-dependent Ser240 phosphorylation site. 14-3-3 binding to Rnd3 also involves phosphorylation of Ser218 by ROCK and/or Ser210 by protein kinase C (PKC). The crystal structure of a phosphorylated, farnesylated Rnd3 peptide with 14-3-3 reveals a hydrophobic groove in 14-3-3 proteins accommodating the farnesyl moiety. Functionally, 14-3-3 inhibits Rnd3-induced cell rounding by translocating it from the plasma membrane to the cytosol. Rnd1, Rnd2, and geranylgeranylated Rap1A interact similarly with 14-3-3. In contrast to the canonical GTP/GDP switch that regulates most Ras superfamily members, our results reveal an unprecedented mechanism for G protein inhibition by 14-3-3 proteins