Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Authors: Town, Jennifer; Pais, Helio; Harrison, Sally; Stead, Lucy F.; Bataille, Carole; Bunjobpol, Wilawan; Zhang, Jing; Rabbitts, Terence H.
Abstract
The cell surface proteome of tumors mediates the interface between the transformed cells and the general microenvironment, including interactions with stromal cells in the tumor niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumor type and potential proteins that can be the target of antibody-mediated therapy. We have used next-generation deep RNA sequencing (RNA-seq) coupled to an inhouse database of genes encoding cell surface proteins (herein referred to as the surfaceome) as a tool to define a cell surface proteome of Ewing sarcoma compared with progenitor mesenchymal stem cells. This subtractive RNA-seq analysis revealed a specific surfaceome of Ewing and showed unexpectedly that the leucine-rich repeat and Ig domain protein 1 (LINGO1) is expressed in over 90% of Ewing sarcoma tumors, but not expressed in any other somatic tissue apart from the brain. We found that the LINGO1 protein acts as a gateway protein internalizing into the tumor cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. Therefore, LINGO1 is a new, unique, and specific biomarker and drug target for the treatment of Ewing sarcoma.
Genetics of Parkinson's disease and essential tremor
CURRENT OPINION IN NEUROLOGY
Authors: Zimprich, Alexander
Abstract
Purpose of review This review summarizes some key findings of the past few years on the genetics of the two common movement disorders Parkinson's disease and essential tremor. Recent findings Within the last two years, genome-wide association (GWA) analyses have revealed a number of novel low-risk susceptibility variants for Parkinson's disease, among them HLA-DRB5, BST1, ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R) and have confirmed LINGO1 as risk factor for essential tremor. The identification of copy number variations in the Parkin gene in healthy control individuals suggests no major role of these variations in late onset Parkinson's disease. Drosophila studies on Parkin and Pink1 have uncovered a role in the mitochondrial quality control pathway in the pathogenesis of the disease. LRRK2 has been found to interact with the microRNAs processing protein Argonaut, thereby affecting protein translation. Notably, despite the high familial risk for essential tremor no high-risk gene has been found to date. The possibility of a nonmendelian transmission in some cases is discussed. Summary GWA studies and positional cloning approaches have led to the identification of a number of risk genes for Parkinson's disease, which give novel insights into pathogenic pathways of the disease. In contrast, our knowledge of the genetics of essential tremor is scarce. Except for LINGO1, no other risk gene has so far been identified. New technologies such as next generation high throughput sequencing might help to identify more risk genes.