Das Stipendium von Frau Katharine Miller wurde ermöglicht durch eine großzügige Zuwendung der Alfred Dollwet Stiftung, Mainz.
TDP-43 and TranslationalControl in FTLD, ALS and Related Neurodegenerative Disorders
Frontotemporal Lobar Degeneration (FTLD) is the second most common cause of presenile onset dementia after Alzheimer’s disease. Recent groundbreaking work supports a major role for the RNA-binding protein (RBP) TDP-43 in FTLD and other major age-related neurological diseases, including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease. TDP-43 is a ubiquitously expressed, largely nuclear protein in healthy cells. In disease, aberrant localization and aggregation of TDP-43 protein are found in affected neurons 1 and disease-causing mutations in TDP-43 have been identified in both FTLD and ALS patients (reviewed in 2). Nevertheless, how TDP-43 contributes to disease remains unclear.
TDP-43’s relocalization from the nucleus to the cytoplasm in disease affected neurons raises a fundamental, unanswered question: is disease due to a loss of nuclear function, gain of cytoplasmic function, or a combination of the two? Since TDP-43 exhibits nuclear/cytoplasmic shuttling ability, it is likely that TDP-43 has important cytoplasmic functions, as has been described for other nuclear RBPs, such as Sex-lethal 3. Indeed, recent genome-wide studies 4,5 revealed that TDP-43 binding sites are also found in mRNA 3’ UTRs, a key region for cytoplasmic regulation of translation by RBPs. Taken together, available data support the idea that TDP-43 may regulate translation of a subset of mRNAs and suggest that aberrant translational regulation by TDP-43 could play an important role in promoting neurodegeneration and disease.
Here I propose to investigate potential cytoplasmic functions of TDP-43 in mRNA-specific translational control in neurons. In my thesis project I aim specifically to:
- Identify mRNAs whose translation is regulated by TDP-43 in neuronal cells
- Determine which mRNAs are bona fide in vivo translational targets of TDP-43 in mice
- Analyze the translational control mechanism used by TDP-43 on its neuronal targets
To achieve these aims I will use a combination of genome-wide and molecular approaches, many of which I have already previously established during my diploma thesis. By first searching for candidates in neuronal cell culture using polysome profiling, I will be able to easily screen for neuronal mRNA targets and rule out false positives. Subsequent focused studies in mouse will allow validation of specific targets in vivo and exploration of the relevance of targets to disease. Through a combination of cell-based assays and cell-free in vitro translation methods, insight into the underlying molecular mechanism will be obtained.
Through this study, I hope to elucidate TDP-43’s effects on translation of specific neuronal mRNAs. I expect my findings to greatly enhance our understanding of TDP-43’s neuronal functions, both in health and disease. Moreover, this approach has the potential to identify new targets for therapeutic development to treat these devastating diseases.
|Geburtsort||Wauwatosa, WI, USA|
|Geburtsdatum||05. April 1984|
|seit 2011||Doktorandin zum Thema "Molecular biological research of translational control involved in neurological disorders." am Duncan Laboratory der Universitätsklinik Hamburg-Eppendorf, Zentrum für Molekulare Neurobiologie Hamburg|
|2010 - 2011||Arbeit an der Diplom-/Masterarbeit an der Universitätsklinik Hamburg, Zentrum für Molekulare Neurobiologie Hamburg, Thema: "Molecular biological research of translational control involved in neurological disorders."|
|2008||Bachelor of Arts mit dem Fokus auf "Molecular Biology and Genetics" an der Northwestern University in Evanston, Illinois|
|2006 - 2010||Labortechnikerin am Dallos Laboratory an der Northwestern University, School of Communication in Evanston, Illinois, USA|
|2004-2006||Arbeitsstudie zu "Molecular biological research on protein
interactions in the outer hair cells of mammalian cochlea" im Dallos Laboratory an der Northwestern University, School of Communication in Evanston, Illinois
|2002-2004||Assistentin für die Kollektion und Organisation von Daten zur Kortisonausschüttung als Reaktion auf Stress im Mineka Laboratory an der Northwestern University, Weinberg College of Arts and Sciences in Evanston, Illinois|
1. CEACAM16 is associated with the Tectorial Membrane and Deafness Locus DFNA4.
Jing Zheng*, Katharine K. Miller*, Tao Yang, P. Kevin Legan, Richard Goodyear, Guy Richardson, MaryAnn Cheatham, Richard J.H. Smith, Peter Dallos. Proc Natl Acad Sci, U.S A. 2011 Mar 8;108(10):4218-23. Epub 2011 Feb 22
*indicates co-first authorship
2. Interaction Between the Motor Protein Prestin and the Transporter Protein Vapa.
Soma Sengupta*, Katharine K. Miller*, MaryAnn Cheatham, Peter Dallos, Jing Zheng. Biochim Biophys Acta, volume 1803 No. 7. pp 796-804. July 2010.
*indicates co-first authorship
3. Interaction between CFTR and Prestin (SLC26A5).
Kazuaki Homma, Katharine K. Miller, Charles T. Anderson, Soma Sengupta, Guo-Guang Du, Salvador Aguinaga, MaryAnn Cheatham, Peter Dallos, Jing Zheng. Biochim Biophys Acta, volume 1798
No. 6. pp. 1029-40. June 2010.
4. EHD4 and CDH23 Are Interacting Partners in Cochlear Hair Cells.
Soma Sengupta, Manju George, Katharine K. Miller, Khurram Naik, Jonathan Chou, MaryAnn Cheatham, Peter Dallos, Mayumi Naramura, Hamid Band, and Jing Zheng. The
Journal of Biological Chemistry, volume 284 No. 30. pp 20121-20129. 24 July 2009
5. Identifying Components of the Hair-Cell Interactome Involved in Cochlear Amplification.
Jing Zheng, Charles T. Anderson, Katharine K. Miller, MaryAnn Cheatham, Peter Dallos. BMC Genomics, 25 March 2009.