The role of TDP43 in neurological disease and brain aging
2 PhD projects offered in the IPP summer call Molecular Mechanisms in Genome Stability & Gene Regulation
Scientific background
Nuclear loss or cytosolic aggregates of the RNA-binding protein TDP-43 are central hallmark neurological diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that TDP-43 dysfunction or aggregation may be an important determinant of healthy vs. pathological aging, and that by influencing the degree of this TDP-43 dysfunction / aggregation, it may be possible to shift neuronal pathologies toward a healthier trajectory. A detailed understanding of the molecular mechanisms and cellular consequences of TDP-43 dysfunction and aggregation is therefore critical for identifying potential diagnostic and therapeutic strategies.
A key determinant and indicator of brain health is the ability to maintain normal excitability of neuronal networks. Indeed, cortical hyperexcitability is an early feature of several neurodegenerative disorders, including ALS and FTD, and it can precede and predict disease progression. Early evidence in mouse models showed that TDP-43 overexpression can induce hyperexcitability and subsequent functional decline, indicating that altering network excitability may be one of the pathological mechanisms of TDP-43 aggregation. To date, however, little is known about this process, and several critical questions remain unanswered.
(1) First, it is currently unclear whether TDP-43-associated pathology results from a loss of normal TDP-43 functions, which include regulation of a wide range of steps in RNA processing, or from a gain of pathological processes induced by the cytoplasmic aggregates, such as disturbances of cellular proteostasis mechanisms.
(2) Second, it is unknown whether and why different populations of neurons show selective vulnerability to TDP-43 dysfunction / aggregation, as suggested by the involvement of specific neurons in diseases associated with TDP-43.
(3) Third, the mechanisms regulating and modulating cytosolic TDP-43 condensation and aggregation remain poorly understood. It has been shown that post-translational modifications, such as phosphorylation and ubiquitination play an important role in determining the formation and clearance of TDP-43 condensates / aggregates, but the key players in this process have yet to be defined. Enhancing TDP-43 clearance or modulating its condensation properties may alter the impact of TDP-43 on network excitability, and may therefore represent an interesting potential target for pharmacotherapies to treat age-dependent degenerative disorders.
PhD project 1: The role of TDP43 in neurological disease and aging, from in vitro studied to in vivo models in the fly (Marion Silies/ Dorothee Dormann)
PhD project 2: The role of TDP43 in neurological disease and aging, from in vitro studied to in vivo models in the mouse (Axel Methner)
We aim to address the above question in a multidisciplinary team that bridges two fields, i.e. the molecular and cellular biology of TDP-43 function and the study of neuronal networks and their functional output. We combine the expertise of five PIs - Dorothee Dormann, Marion Silies, Dilja Krueger-Burg, Axel Methner, and Michael Schmeisser - to span from in vitro assays to behavioral analysis
- using the fruit fly Drosophila as a model system (PhD 1 project),
- or using mouse models (PhD project 2),
allowing us to link molecular, cellular, network and behavioral dysfunction, and to also directly test strategies to counteract TDP-43-mediated dysfunctions that are detrimental to healthy aging.
If you are interested in project 1, please select Silies/Dormann as your group preference in the IPP application platform.
If you are interested in project 2, please select Methner (TDP) as your group preference in the IPP application platform.
Publications relevant to the project
Work from the Dormann lab, characterizing TDP-43 condensation / aggregation states:
Gruijs da Silva LA, Simonetti F, Hutten S, Riemenschneider H, Sternburg EL, Pietrek LM, Gebel J, Dötsch V, Edbauer D, Hummer G, Stelzl LS and Dormann D (2022) Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation. EMBO J, 41:e108443 Link
Two example publications from the Silies and Krueger-Burg labs, performing in vivo characterizations of neural circuits / neuronal activity:
Henning M, Ramos-Traslosheros G, Gür B, Silies M (2022) Populations of local direction-selective cells encode global motion patterns generated by self-motion. Science Advances 8:3. doi: 10.1126/sciadv.abi7112 Link
Babaev O, Cruces-Solis H, Piletti Chatain C, Hammer M, Wenger S, Ali H, Karalis N, de Hoz L, Schlüter OM, Yanagawa Y, Ehrenreich H, Taschenberger H, Brose N and Krueger-Burg D (2018) IgSF9b regulates anxiety behaviors through effects at centromedial amygdala inhibitory synapses.Nat. Commun. 9:5400 Link