The main focus of my research is to decipher mechanisms of neuronal degeneration and identify molecular interventions that prevent neuronal damage.
My lab is interested in the study of dopaminergic neurons, from the transcriptional programs that regulate their differentiation in development, to the molecular mechanisms that safeguard their structural and functional integrity throughout life.
The dopaminergic neurons are involved in an array of behavioural processes, for example controlling voluntary movement, reward, mood, addiction, etc. Importantly, their loss leads to one of the most prominent human neurological conditions in humans, namely Parkinson’s disease.
We study the molecular underpinnings of dopaminergic neurodegeneration using C. elegans as a model organism. The detailed knowledge of C. elegans anatomy, its transparency and the powerful molecular genetic tools, allow the observation and study of neuronal morphology and function in living animals, at a high resolution. The C. elegans hermaphrodite contains precisely 8 dopaminergic neurons (Image 1). Despite the simplicity of its nervous system, there is high conservation at the level of gene expression and biochemical pathways between C. elegans and humans.
To discover novel genetic pathways involved in neurodegeneration and neuroprotection we use high-throughput molecular genetics. We carry out unbiased forward genetic screens empowered by the COPAS Biosort technology (worm sorter), which allows rapid mutant isolation (Image 2), followed by whole genome sequencing for mutant identification.
We have recently identified a gain-of-function mutation in a Transient Receptor Potential channel, trp-4, that causes dopamine neurons to progressively degenerate, through a calcium-related downstream mechanism (Image 3). Making use of the trp-4 model, and also of other mutations in orthologs of human genes linked to familial Parkinson’s disease, we are pursuing two main objectives:
A. Understand the cellular pathways that lead to neuronal cell death in Parkinson’s disease and other neurodegenerative disorders, B. Discover molecular interventions that delay or stop the progression of neuronal degeneration.
Nagarajan A, Ning Y, Reisner K, Larsen JP, Hobert O, Doitsidou M ¶ Progressive degeneration of dopaminergic neurons through TRP channel-induced cell death. J Neuroscience. 2014 Apr 23;34(17): 5738-46.
Doitsidou M*¶, Flames N*¶, Topalidou N, Abe N, Felton T, Remesal L, Popovitchenko T, Mann R, Chalfie M and Hobert O. A combinatorial regulatory signature controls terminal differentiation of the dopaminergic nervous system in C. elegans. Genes and Development. 2013 Jun 15;27(12):1391-405.
Boldajipour B*, Doitsidou M*, Tarbashevich* K, Laguri C, Yu SR, Ries J, Dumstrei K, Thelen S, Dörries J, Messerschmidt EM, Thelen M, Schwille P, Brand M, Lortat-Jacob H, Raz E. Cxcl12 evolution - subfunctionalization of a ligand through altered interaction with the chemokine receptor. Development. 2011 Jul;138(14):2909-14.
Doitsidou M ¶, Poole JR, Sarin S, Bigelow H and Hobert O. C. elegans mutant identification with a one-step Whole-Genome-Sequencing and SNP mapping strategy. PLoS ONE. 2010 Nov 8;5(11):e15435. Sarin S, Bertrand V, Bigelow H, Boyanov A, Doitsidou M, Poole R, Narula S and Hobert O. Analysis of EMS-mutagenized C. elegans strains by whole genome sequencing. Genetics. 2010 Jun;185(2):417-30.
Bigelow H, Doitsidou M, Sarin S, Hobert O. MAQGene: software to facilitate C. elegans mutant genome sequence analysis. Nature Methods. 2009 Aug;6(8):549.
Doitsidou M ¶, Flames N, Lee AC, Boyanov A, Hobert O. Automated screening for mutants affecting dopaminergic neuron specification in C. elegans. Nature Methods. 2008 Oct;5(10):869-72.
Thorpe JL*, Doitsidou M*, Ho SY, Raz E and Farber SA. Germ Cell Migration in Zebrafish Is Dependent on HMGCoA Reductase Activity and Prenylation. Developmental Cell. 2004 Feb;6(2):295-302.
van Oers MM, Doitsidou M, Thomas AA, de Maagd RA, Vlak JM. Translation of both 5'TOP and non-TOP host mRNAs continues into the late phase of Baculovirus infection. Insect Molecular Biology. 2003 Feb;12(1):75-84.
Doitsidou M, Reichman-Fried M, Stebler J, Köprunner M, Dörries J, Meyer D, Esguerra VC, Leung T and Raz E. Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 2002 Nov 27;111(5):647-59.
¶: corresponding author, * equally contributing