News

graduationCongratulations on your PhD!
 

Joanna Liwocha

 

Mechanisms of polyubiquitin chain formation

RG: Brenda Schulman

 


 

graduationCongratulations on your PhD!
 

Verónica Solís González

 

Understanding the role of epithelial MyD88 signals in the early development of Experimental Autoimmune Encephalomyelitis (EAE)

RG: Hartmut Wekerle

 


 

  

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Hees, J.T., and Harbauer, A.B.
Biomolecules, 2022, 12, 1595.
doi: 10.3390/biom12111595

Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective

Neurons critically depend on mitochondria for ATP production and Ca2+ buffering. They are highly compartmentalized cells and therefore a finely tuned mitochondrial network constantly adapting to the local requirements is necessary. For neuronal maintenance, old or damaged mitochondria need to be degraded, while the functional mitochondrial pool needs to be replenished with freshly synthesized components. Mitochondrial biogenesis is known to be primarily regulated via the PGC-1α-NRF1/2-TFAM pathway at the transcriptional level. However, while transcriptional regulation of mitochondrial genes can change the global mitochondrial content in neurons, it does not explain how a morphologically complex cell such as a neuron adapts to local differences in mitochondrial demand. In this review, we discuss regulatory mechanisms controlling mitochondrial biogenesis thereby making a case for differential regulation at the transcriptional and translational level. In neurons, additional regulation can occur due to the axonal localization of mRNAs encoding mitochondrial proteins. Hitchhiking of mRNAs on organelles including mitochondria as well as contact site formation between mitochondria and endolysosomes are required for local mitochondrial biogenesis in axons linking defects in any of these organelles to the mitochondrial dysfunction seen in various neurological disorders.

 


 

graduationCongratulations on your PhD!
 

Anna Kolz

 

T:B cell communication in ectopic lymphoid follicles in CNS autoimmunity

RG: Anneli Peters

 


 

graduationCongratulations on your PhD!
 

Thomas van Emden

 

Regulation of Transcription and Stability of Repetitive DNA in S. pombe

RG: Sigurd Braun

 


 

graduationCongratulations on your PhD!
 

Martina Peritore

 

Strand-specific ChIP-sequencing reveals nucleosome dynamics at DNA double-strand breaks

RG: Boris Pfander

 


 

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Brüggenthies, J.B., Fiore, A., Russier, M., Bitsina, C., Brötzmann, J., Kordes, S., Menninger, S., Wolf, A., Conti, E., Eickhoff, J.E., and Murray, P.J.
(IMPRS-LS students are in bold)
J Biol Chem, 2022, 102629
doi: 10.1016/j.jbc.2022.102629

A cell-based chemical-genetic screen for amino acid stress response inhibitors reveals torins reverse stress kinase GCN2 signaling

mTORC1 and GCN2 are serine/threonine kinases that control how cells adapt to amino acid availability. mTORC1 responds to amino acids to promote translation and cell growth while GCN2 senses limiting amino acids to hinder translation via eIF2α phosphorylation. GCN2 is an appealing target for cancer therapies because malignant cells can harness the GCN2 pathway to temper the rate of translation during rapid amino acid consumption. To isolate new GCN2 inhibitors, we created cell-based, amino acid limitation reporters via genetic manipulation of Ddit3 (encoding the transcription factor CHOP). CHOP is strongly induced by limiting amino acids and in this context, GCN2-dependent. Using leucine starvation as a model for essential amino acid sensing, we unexpectedly discovered ATP-competitive PI3 kinase-related kinase inhibitors, including ATR and mTOR inhibitors like torins, completely reversed GCN2 activation in a time-dependent way. Mechanistically, via inhibiting mTORC1-dependent translation, torins increased intracellular leucine, which was sufficient to reverse GCN2 activation and the downstream integrated stress response including stress-induced transcriptional factor ATF4 expression. Strikingly, we found that general translation inhibitors mirrored the effects of torins. Therefore, we propose that mTOR kinase inhibitors concurrently inhibit different branches of amino acid sensing by a dual mechanism involving direct inhibition of mTOR and indirect suppression of GCN2 that are connected by effects on the translation machinery. Collectively, our results highlight distinct ways of regulating GCN2 activity.

 


 

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Kohyama, S.#, Merino-Salomón, A.#, and Schwille, P.
# equal contribution
Nat Commun, 2022, 13, 6098.
doi: 10.1038/s41467-022-33679-x

In vitro assembly, positioning and contraction of a division ring in minimal cells

Constructing a minimal machinery for autonomous self-division of synthetic cells is a major goal of bottom-up synthetic biology. One paradigm has been the E. coli divisome, with the MinCDE protein system guiding assembly and positioning of a presumably contractile ring based on FtsZ and its membrane adaptor FtsA. Here, we demonstrate the full in vitro reconstitution of this machinery consisting of five proteins within lipid vesicles, allowing to observe the following sequence of events in real time: 1) Assembly of an isotropic filamentous FtsZ network, 2) its condensation into a ring-like structure, along with pole-to-pole mode selection of Min oscillations resulting in equatorial positioning, and 3) onset of ring constriction, deforming the vesicles from spherical shape. Besides demonstrating these essential features, we highlight the importance of decisive experimental factors, such as macromolecular crowding. Our results provide an exceptional showcase of the emergence of cell division in a minimal system, and may represent a step towards developing a synthetic cell.

 


 

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Voelkl, K., Schulz-Trieglaff, E.K., Klein, R., and Dudanova, I.
(IMPRS-LS students in bold)
Front Neurosci, 2022, 16, 1022251.
doi: 10.3389/fnins.2022.1022251

Distinct histological alterations of cortical interneuron types in mouse models of Huntington's disease

Huntington's disease (HD) is a debilitating hereditary motor disorder caused by an expansion of the CAG triplet repeat in the Huntingtin gene. HD causes neurodegeneration particularly in the basal ganglia and neocortex. In the cortex, glutamatergic pyramidal neurons are known to be severely affected by the disease, but the involvement of GABAergic interneurons remains unclear. Here, we use a combination of immunostaining and genetic tracing to investigate histological changes in three major cortical interneuron types - parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) interneurons - in the R6/2 and zQ175DN mouse models of HD. In R6/2 mice, we find a selective reduction in SST and VIP, but not PV-positive cells. However, genetic labeling reveals unchanged cell numbers for all the interneuron types, pointing to molecular marker loss in the absence of cell death. We also observe a reduction in cell body size for all three interneuron populations. Furthermore, we demonstrate progressive accumulation of mutant Huntingtin (mHTT) inclusion bodies in interneurons, which occurs faster in SST and VIP compared to PV cells. In contrast to the R6/2 model, heterozygous zQ175DN knock-in HD mice do not show any significant histological changes in cortical cell types at the age of 12 months, apart from the presence of mHTT inclusions, which are abundant in pyramidal neurons and rare in interneurons. Taken together, our findings point to differential molecular changes in cortical interneuron types of HD mice.

 


 

graduationCongratulations on your PhD!
 

Lorenzo Galanti

Role of DDK kinase in DNA double-strand break repair and insights into the DDK-Cdc5/PLK1 kinase complex

RG: Boris Pfander