Research Summary

Role of intracellular signaling lipids in membrane trafficking in normal and diseased neurons.

Lipid-mediated signaling regulates a plethora of cellular processes, including organelle trafficking, signal transduction and cytoskeletal dynamics. Consistent with a central role of intracellular regulatory lipids in cell physiology, dysregulation of their metabolism has been implicated in a growing number of diseases, including neurodegenerative disorders. Research in my laboratory focuses on the analysis of major bioactive phospholipids, such as phosphoinositides and phosphatidic acid, and their role in the regulation of membrane trafficking to and from the plasma membrane as well as along the endolysosomal and autophagy pathways. We study intracellular lipid signaling primarily in neurons in order to understand the molecular and cellular mechanisms controlling normal synaptic function. We also study how perturbations in such signaling can lead to synaptic malfunction, neurodegeneration and cognitive decline in Down syndrome and Alzheimer's disease. To tackle these fundamental questions, we employ multidisciplinary approaches, which range from molecular and cell biology, protein and lipid biochemistry (including 'lipidomics') to mouse genetics and behavioral assessments of genetically-modified mice.

Selected Publications

1. Di Paolo G, Moskowitz H, Gipson K, Wenk MR, Voronov S, Obayashi M, Flavell R, Fitzsimonds R, Ryan TA, De Camilli P. Impaired PtdIns(4,5)P(2) synthesis in nerve terminals produces synaptic vesicle trafficking defects. Nature (2004); 431: 415-22.

2. Di Paolo G, De Camilli. Phosphoinositides in cell regulation and membrane dynamics. Nature (2006); 443, 651-657.

3. Landman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, Park MK,
Di Paolo G, Chung S, Kim TW. Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol-4,5-bisphosphate metabolism. PNAS, (2006) 103,19524-19529.

4. Berman DE, Dall'Armi C, Voronov SV, McIntire LB, Zhang H, Moore AZ, Staniszewski A, Arancio O, Kim TW, Di Paolo G. Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nat. Neurosci. (2008); 11; 521-617.

5. Voronov SV, Frere SG, Giovedi S, Pollina EA, Borel C, Zhang H, Schmidt C, Akeson EC, Wenk MR, Arancio O, Davisson MT, Antonarakis SE, Gardiner K, De Camilli P, Di Paolo G. Synj1-linked PI(4,5)P2 Dyshomeostasis and Cognitive Deficits in Genetic Models of Down Syndrome. PNAS (2008) 105, 9415-9420.

6. Allaire PD, Marat AL, Dall'Armi C, Di Paolo G, McPherson PS, Ritter B. The connecdenn DENN domain: a GEF for Rab35 mediating cargo-specific exit from early endosomes. Molecular Cell (2010); 37, 370-382.

7. Oliveira TG, Di Paolo G. Phospholipase D in brain function and Alzheimer's disease. Biochimica et Biophysica Acta (2010); 1801, 799-805.

8. Oliveira TG, Chan RB, Tian H, Laredo M, Shui G, Staniszewski A, Zhang A, Wang L, Kim TW, Duff KE, Arancio O, Di Paolo G. Phospholipase D2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits. J. Neurosci. (2010); 16419-28.

9. Dall-Armi C, Hurtado-Lorenzo A, Tian H, Morel E, Nezu, A, Chan RB, Yu WH, Robinson KS, Yeku O, Small SA, Duff K, Frohman MA, Wenk MR, Yamamoto A, Di Paolo G. Phospholipase D1 modulates macroautophagy. Nature Commun. (2010). DOI: 10.1038/ncomms1144.

10. Chang-Ileto B, Frere SG, Chan RB, Voronov SV, Roux A, Di Paolo G. Synaptojanin 1-mediated PI(4,5)P2 hydrolysis is modulated by membrane curvature and facilitates membrane fission. Developmental Cell (2011); 20, 206–218.

11. Di Paolo G, Kim TW. Linking Lipids to Alzheimer’s Disease: Cholesterol and Beyond. Nature Rev Neurosci (2011); 12: 284-96

12. Chan RB, Oliveira TG, Duff K, Small SA, Wenk MR, Shui G, Di Paolo G. Comparative lipidomic analysis of mouse and human brain with Alzheimer's disease. J. Biol Chem (2012); 287: 2678-88.

13. Rodriguez-Navarro JA, Kaushik S, Dall’Armi C, Koga H, Shui G, Wenk MR, Di Paolo G, Cuervo AM. Inhibitory effect if dietary lipids on Chaperone-mediated Autophagy. PNAS (2012); 109: E705-14.

Honors and Awards

1998 Graduated summa cum laude, University of Lausanne
1998 EMBO long-term Postdoctoral Fellowship
1999 Scientific Merit Award for Outstanding Thesis, University of Lausanne
2003 Yale DERC pilot grant for 2004-2005
2005-2006 Charles J. Epstein Award from the National Down Syndrome Society
2006 Basil O'Connor Young Investigator Award (March of Dimes)
2006 Whitehall Foundation Award
2007 McKnight Award
2008 Irma T. Hirschl and Monique Weill-Caulier Award

Committees , Council, and Professional Society Memberships

American Society for Cell Biology

Society for Neuroscience

Keywords

Phosphoinositide, phosphatidylinositol-4,5-bisphosphate, diacylglycerol, endocytosis, exocytosis, synapse, synaptic vesicle, clathrin, Down syndrome, Alzheimer's disease, neurodegeneration, synaptojanin, autophagy
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