PICALM Modulates Autophagy Activity and Tau Accumulation

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Sep 23

PMID 25241929

Citations 129

Authors

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 OKane

Daniel S Wechsler

David C Rubinsztein

Affiliations

Soon will be listed here.

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.

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References

Yen W, Shintani T, Nair U, Cao Y, Richardson B, Li Z . The conserved oligomeric Golgi complex is involved in double-membrane vesicle formation during autophagy. J Cell Biol. 2010; 188(1):101-14. PMC: 2812853. DOI: 10.1083/jcb.200904075. View

Narain Y, Wyttenbach A, Rankin J, Furlong R, Rubinsztein D . A molecular investigation of true dominance in Huntington's disease. J Med Genet. 1999; 36(10):739-46. PMC: 1734229. DOI: 10.1136/jmg.36.10.739. View

Suzuki M, Tanaka H, Tanimura A, Tanabe K, Oe N, Rai S . The clathrin assembly protein PICALM is required for erythroid maturation and transferrin internalization in mice. PLoS One. 2012; 7(2):e31854. PMC: 3283694. DOI: 10.1371/journal.pone.0031854. View

Kimmel C, Ballard W, Kimmel S, Ullmann B, Schilling T . Stages of embryonic development of the zebrafish. Dev Dyn. 1995; 203(3):253-310. DOI: 10.1002/aja.1002030302. View

Sahlender D, Kozik P, Miller S, Peden A, Robinson M . Uncoupling the functions of CALM in VAMP sorting and clathrin-coated pit formation. PLoS One. 2013; 8(5):e64514. PMC: 3669311. DOI: 10.1371/journal.pone.0064514. View

Freeman M . Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell. 1996; 87(4):651-60. DOI: 10.1016/s0092-8674(00)81385-9. View

Parkes T, Elia A, Dickinson D, Hilliker A, Phillips J, Boulianne G . Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet. 1998; 19(2):171-4. DOI: 10.1038/534. View

Suri C, Fung B, Tischler A, Chikaraishi D . Catecholaminergic cell lines from the brain and adrenal glands of tyrosine hydroxylase-SV40 T antigen transgenic mice. J Neurosci. 1993; 13(3):1280-91. PMC: 6576599. View

Rubinsztein D, Cuervo A, Ravikumar B, Sarkar S, Korolchuk V, Kaushik S . In search of an "autophagomometer". Autophagy. 2009; 5(5):585-9. DOI: 10.4161/auto.5.5.8823. View

10.

Ravikumar B, Sarkar S, Davies J, Futter M, Garcia-Arencibia M, Green-Thompson Z . Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010; 90(4):1383-435. DOI: 10.1152/physrev.00030.2009. View

11.

Puri C, Renna M, Bento C, Moreau K, Rubinsztein D . Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell. 2013; 154(6):1285-99. PMC: 3791395. DOI: 10.1016/j.cell.2013.08.044. View

12.

van der Vaart A, Griffith J, Reggiori F . Exit from the Golgi is required for the expansion of the autophagosomal phagophore in yeast Saccharomyces cerevisiae. Mol Biol Cell. 2010; 21(13):2270-84. PMC: 2893990. DOI: 10.1091/mbc.e09-04-0345. View

13.

Lee T, Luo L . Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron. 1999; 22(3):451-61. DOI: 10.1016/s0896-6273(00)80701-1. View

14.

Spilman P, Podlutskaya N, Hart M, Debnath J, Gorostiza O, Bredesen D . Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One. 2010; 5(4):e9979. PMC: 2848616. DOI: 10.1371/journal.pone.0009979. View

15.

Zhang B, Koh Y, Beckstead R, Budnik V, Ganetzky B, Bellen H . Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis. Neuron. 1999; 21(6):1465-75. DOI: 10.1016/s0896-6273(00)80664-9. View

16.

Cadwell K, Liu J, Brown S, Miyoshi H, Loh J, Lennerz J . A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008; 456(7219):259-63. PMC: 2695978. DOI: 10.1038/nature07416. View

17.

Schjeide B, Schnack C, Lambert J, Lill C, Kirchheiner J, Tumani H . The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels. Arch Gen Psychiatry. 2011; 68(2):207-13. DOI: 10.1001/archgenpsychiatry.2010.196. View

18.

Scotland P, Heath J, Conway A, Porter N, Armstrong M, Walker J . The PICALM protein plays a key role in iron homeostasis and cell proliferation. PLoS One. 2012; 7(8):e44252. PMC: 3431333. DOI: 10.1371/journal.pone.0044252. View

19.

Cerda G, Thomas J, Allende M, Karlstrom R, Palma V . Electroporation of DNA, RNA, and morpholinos into zebrafish embryos. Methods. 2006; 39(3):207-11. DOI: 10.1016/j.ymeth.2005.12.009. View

20.

Utton M, Connell J, Asuni A, van Slegtenhorst M, Hutton M, de Silva R . The slow axonal transport of the microtubule-associated protein tau and the transport rates of different isoforms and mutants in cultured neurons. J Neurosci. 2002; 22(15):6394-400. PMC: 6758152. DOI: 20026670. View