401C, Life Sciences Center
Aging cells change their metabolic rates, vesicular trafficking, and signaling – all of these factors contribute to the onset and progression of human diseases, such as Alzheimer’s or cancer. Our lab is interested in the molecular mechanisms leading to neuronal death as observed in Alzheimer’s and Parkinson’s disease (AD and PD), the two most common neurodegenerative disorders. Surprisingly, only very little is known about the molecular cause and still, no cure exists for these diseases. Understanding molecular changes leading to the known pathologic phenotypes observed in AD or PD is the key to develop new drugs and help patients. Only recently, changes in the endo-lysosomal pathway have been described to be involved in the onset of these two disorders and are discussed to be one of the very first molecular changes detected in the diseased brains. The endo-lysosomal pathway is the cellular system taking up molecules (like proteins) from the outside or inside of the cell and digesting them in the lysosome (an organelle often described as the stomach of the cell) or sorting those molecules to its diverse compartments. The endo-lysosomal system is tightly connected to the receptor-mediated signaling through the shuttling of the receptors from the plasma membrane to endosomes which are, in many cases, specific signaling platforms. It is clear that changes in the endo-lysosomal system modify signaling outcomes in the AD and PD brains. The long-term goal of our lab is to define the molecular mechanisms leading to changes in major cellular signaling pathways regulating protein stability and trafficking in AD and PD. We investigate these alterations in neurons that we obtain from mice or through direct reprogramming of patients’ fibroblasts. ** We are currently accepting students who are interested in joining our lab for their Ph.D. thesis work.Please check our lab website: http://www.dobrowolskilab.com/
Diploma in Biology, University of Bonn, Germany, 2004
Ph.D. in Biology, University of Bonn, under the guidance of Dr. Klaus Willecke, Germany, 2008
Postdoc, University of California, under the guidance of Dr. Edward DeRobertis, Los Angeles, CA, 2012
Nnah IC, Wang B, Saqcena C, Weber GF, Bonder EM, Bagley D, De Cegli R, Napolitano G, Medina DL, Ballabio A, Dobrowolski R. TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy. Autophagy. 2019 Jan;15(1):151-164. doi: 10.1080/15548627.2018.1511504.
Khayati K, Antikainen H, Bonder EM, Weber GF, Kruger WD, Jakubowski H, Dobrowolski R. The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice. FASEB J. 2017 Feb;31(2):598-609.
Reddy K, Cusack CL, Nnah IC, Khayati K, Saqcena C, Huynh TB, Noggle SA, Ballabio A, Dobrowolski R. Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency. Cell Rep. 2016 Mar 8;14(9):2166-2179. doi: 10.1016/j.celrep.2016.02.006. Epub 2016 Feb 25.
R Dobrowolski, P Vick, D Ploper, I Gumper, H Snitkin, DD Sabatini, EM Robertis. Presenilin deficiency or lysosomal inhibition enhances Wnt signaling through relocalization of GSK3 to the late-endosomal compartment. Cell Rep. 2012 Nov 29;2(5):1316-28.
R Dobrowolski, EM De Robertis, Endocytic control of growth factor signalling: multivesicular bodies as signalling organelles., Nat Rev Mol Cell Biol. 2012 Nov 23;13(1):53-60. doi: 10.1038/nrm3244.
Torres A, Wang F, Xu Q, Fujita T, Dobrowolski R, Willecke K, Takano T, Nedergaard M. Extracellular Ca2+ acts as a mediator of communication from neurons to glia. Sci Signal. 2012 Jan 24;5(208):ra8.
Taelman VF, Dobrowolski R, Plouhinec JL, Fuentealba LC, Vorwald PP, Gumper I, Sabatini DD, De Robertis EM. Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes. Cell. 2010 Dec 23;143(7):1136-48.
Dobrowolski R, Hertig G, Lechner H, Wörsdörfer P, Wulf V, Dicke N, Eckert D, Bauer R, Schorle H, Willecke K. Loss of connexin43-mediated gap junctional coupling in the mesenchyme of limb buds leads to altered expression of morphogens in mice. Hum Mol Genet. 2009 Aug 1;18(15):2899-911. Epub 2009 May 12
Dobrowolski R, Sasse P, Schrickel JW, Watkins M, Kim JS, Rackauskas M, Troatz C, Ghanem A, Tiemann K, Degen J, Bukauskas FF, Civitelli R, Lewalter T, Fleischmann BK, Willecke K. The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans. Hum Mol Genet. 2008 Feb
15;17(4):539-54. Epub 2007 Nov 13.