Dr. Meike Broemer
Group Leader
German Center for Neurodegenerative Diseases (DZNE)
Carl-Troll-Straße 31
53115 Bonn
meike.broemer(at)dzne.de
+49 (0) 228 / 73 - 62741
+49 (0) 228 / 73 - 62641
More information
Areas of investigation/research focus
The aim of our research programme is to improve our understanding of how ubiquitin and ubiquitin-like proteins contribute to prevention and pathogenesis of neurodegenerative diseases.
Posttranslational modification of proteins with ubiquitin (Ub) and ubiquitin-like (UBL) molecules is an important regulatory element for a large number of physiological processes. Over the recent years, it has become clear that Ub does not only target proteins for proteasomal degradation but also serves as a versatile adduct to influence signalling events, for example by altering a protein’s subcellular localisation, enzyme activity or binding pattern. The consequence of Ub/UBL conjugation largely depends on the type of modification (mono- vs. poly-ubiquitylation) and the chain linkage within poly-Ub chains. Proteins with specialised Ub-binding domains serve as ‘reader’ of the message (or Ub-receptors) and link modified proteins to downstream signalling.
- Figure: Ubiquitin-dependent signalling. Ubiquitin E3-ligases attach ubiquitin (Ub) to target proteins. The recognition of Ub by specialised Ub-receptors determines the consequence of ubiquitylation which can lead to proteasomal degradation or signalling events. Ub chains can be removed by de-ubiquitylating enzyms (DUBs)
Several findings indicate a crucial role for ubiquitin-dependent processes in neurodegenerative diseases.
A hallmark of neurodegeneration is the accumulation of protein aggregates in combination with impaired activity of the Ubiquitin-Proteasome system. Furthermore, mutations in ubiquitin-related genes such as the E3-ligase Parkin and the de-ubiquitylating enzyme Ataxin-3 are disease-causing events in some familial cases of Parkinson’s disease and Spinocerebellar ataxia type 3, respectively. In addition, the de-ubiquitylating enzyme UCH-L1 is one of the most abundant neuronal proteins, demonstrating a crucial role of this class of proteins in neurons.
Recently, genome-wide screens have identified a number of Ub-related genes as modifiers of neurodegenerative phenotypes in vivo. Nevertheless it is currently not well understood how defects in Ubiquitin conjugation and de-conjugation lead to disease or promote its progression. Particularly degradation-independent functions of ubiquitylation (depending on the type of linkage in the poly-Ub chain) have rarely been studied in this context. Similarly, the role of Ubiquitin-like proteins in neurodegeneration has not been addressed so far.
We are using a synergistic approach using various model systems to address how the conjugation and de-conjugation of Ub and UBL proteins modulates cellular processes that lead to or prevent neurodegenerative diseases.
Drosophila melanogaster provides a powerful genetic tool to obtain in vivo data of evolutionarily conserved pathways. Fly models for human degenerative diseases have been well established, e.g. for polyQ-type diseases, for example Spinocerebellar Ataxia SCA1, SCA3, or Huntington Disease. These fly models will be used as a starting point to obtain new data regarding the role of Ub-related processes in the pathogenesis of degenerative diseases. Molecular mechanisms will be deciphered using techniques of biochemistry, molecular and cell biology and proteomics, followed by in vivo validation.
Publications
CARD-mediated autoinhibition of cIAP1’s E3 ligase activity suppresses cell proliferation and migration.
Lopez J, John SW, Tenev T, Rautureau GJ, Hinds MG, Francalanci F, Wilson R, Broemer M, Santoro MM, Day CL, Meier P., Mol Cell. 2011 Jun 10;42(5):569-83.
Systematic in vivo RNAi analysis identifies IAPs as NEDD8-E3 ligases.
Broemer M, Tenev T, Rigbolt KT, Hempel S, Blagoev B, Ditzel M, Meier P., Mol Cell. 2010 Dec 10;40(5):810-22.
Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling.
Paquette N, Broemer M, Aggarwal K, Chen L, Husson M, Ertürk-Hasdemir D, Reichhart JM, Meier P, Silverman N., Mol Cell. 2010 Jan 29;37(2):172-82.
Identification of a chemokine receptor profile characteristic for mediastinal large B-cell lymphoma.
Rehm A, Anagnostopoulos I, Gerlach K, Broemer M, Scheidereit C, Jöhrens K, Hübler M, Hetzer R, Stein H, Lipp M, Dörken B, Höpken UE., Int J Cancer. 2009 Nov 15;125(10):2367-74.
Two roles for the Drosophila IKK complex in the activation of Relish and the induction of antimicrobial peptide genes.
Ertürk-Hasdemir D, Broemer M, Leulier F, Lane WS, Paquette N, Hwang D, Kim CH, Stöven S, Meier P, Silverman N., Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9779-84. Epub 2009 Jun 2.
Ubiquitin-mediated regulation of apoptosis.
Broemer M, Meier P., Trends Cell Biol. 2009 Mar;19(3):130-40. Epub 2009 Feb 13.
Inactivation of effector caspases through nondegradative polyubiquitylation.
Ditzel M, Broemer M*, Tenev T, Bolduc C, Lee TV, Rigbolt KT, Elliott R, Zvelebil M, Blagoev B, Bergmann A, Meier P., Mol Cell. 2008 Nov 21;32(4):540-53.
*equally contributing first author
Signal responsiveness of IkappaB kinases is determined by Cdc37-assisted transient interaction with Hsp90.
Hinz M, Broemer M*, Arslan SC, Otto A, Mueller EC, Dettmer R, Scheidereit C., J Biol Chem. 2007 Nov 2;282(44):32311-9. Epub 2007 Aug 29.
*equally contributing first author
Requirement of Hsp90 activity for IkB kinase (IKK) biosynthesis and for constitutive and inducible IKK and NF-kB activation.
Broemer M, Krappmann D., Scheidereit C. , Oncogene (2004). 23(31): 5378-86.
The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation.
Holtmann H., Enninga J., Kalble S., Thiefes A., Dorrie A., Broemer M, Winzen R., Wilhelm A., Ninomiya-Tsuji J., Matsumoto K., Resch K., Kracht M. , J Biol Chem. (2001) Feb 2;276(5):3508-16