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3 results on '"Jacob L. Mercer"'

1. Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis.

Author

Jacob L Mercer, Joseph P Argus, Donna M Crabtree, Melissa M Keenan, Moses Q Wilks, Jen-Tsan Ashley Chi, Steven J Bensinger, Catherine P Lavau, and Daniel S Wechsler

Subjects
Medicine, Science
Abstract

PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked PICALM Single Nucleotide Polymorphisms (SNPs) to Alzheimer's disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. Gas Chromatography-Mass Spectrometry (GC-MS) studies indicated that loss of PICALM increases cellular cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters increased net scavenging of cholesterol. Flow cytometry analyses confirmed that internalization of the LDL receptor is enhanced in PICALM-deficient cells as a result of higher levels of LDLR expression. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease.

Published
2015
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2. Correction: Corrigendum: PICALM modulates autophagy activity and tau accumulation

Author

Catherine Lavau, Sara Imarisio, Angeleen Fleming, Jacob L. Mercer, Ana Lopez Ramirez, Daniel S. Wechsler, Eszter Zavodszky, David C. Rubinsztein, Carla F. Bento, Cahir J. O'Kane, Farah H. Siddiqi, Claudia Puri, Kevin Moreau, Maria Jimenez-Sanchez, and Maureen Betton

Subjects
Gene knockdown, Multidisciplinary, biology, Morpholino, Oligonucleotide, Autophagy, General Physics and Astronomy, Translation (biology), Translation start site, General Chemistry, biology.organism_classification, General Biochemistry, Genetics and Molecular Biology, PICALM, Cell biology, Zebrafish
Abstract

Nature Communications 5:4998 doi: 10.1038/ncomms5998 (2014); Published 22 Sep 2014; Updated 28 Jan 2015 The following information was inadvertently omitted from the Methods section in this Article. Knockdown of atg7 in zebrafish. Embryos were injected at the one-cell stage with a translation blocking morpholino oligonucleotide targeted to the translation start site of atg7 (5′-GCTTCAGACTGGATTCCGCCATCGA-3′) or with a 5-bp mismatch control morpholino.

Published
2015
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3. PICALM modulates autophagy activity and tau accumulation

Author

Kevin, Moreau, Angeleen, Fleming, Sara, Imarisio, Ana, Lopez Ramirez, Jacob L, Mercer, Maria, Jimenez-Sanchez, Carla F, Bento, Claudia, Puri, Eszter, Zavodszky, Farah, Siddiqi, Catherine P, Lavau, Maureen, Betton, Cahir J, O'Kane, Daniel S, Wechsler, and David C, Rubinsztein

Subjects
Male, Vesicle-Associated Membrane Protein 2, tau Proteins, Fibroblasts, Transfection, Endocytosis, Cell Line, Mice, HEK293 Cells, Risk Factors, Monomeric Clathrin Assembly Proteins, Phagosomes, Autophagy, Small Ubiquitin-Related Modifier Proteins, Animals, Humans, Drosophila, Female, RNA, Small Interfering, Autophagy-Related Protein 12, Zebrafish, Genome-Wide Association Study, HeLa Cells, Protein Binding
Abstract

Genome-wide association studies have identified several loci associated with Alzheimer's disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover.

Published
2013

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