Studies

Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we establish independent approaches to achieve the functional correction of trimer assembly defects. Focusing on the prototypical R274Q mutation, we identify an HTRA1 variant that promotes trimer formation thus restoring enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrate that expression of this protein-based corrector in trans is sufficient to stabilize ...

Prion-like spreading of protein misfolding is characteristic for neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like ...

Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability and the development of secondary neurodegenerative diseases. A holistic understanding of the mechanisms controlling the responses of specific cell types and their crosstalk is required to develop an efficient strategy for better regeneration. Here, we combine spatial and single-cell transcriptomics to chart the transcriptomic signature of the injured male murine ...

Signal peptide peptidase-like 2c (SPPL2c) is the only member of the GxGD type intramembrane-cleaving aspartyl proteases that so far has not been assigned any substrates and thus its capability of proteolysis and its physiological function remain enigmatic. Based on a surprisingly high expression of SPPL2c in elongated spermatids we applied proteomics on a cellular model system with ectopic expression of SPPL2c and identified a variety of candidate substrates. The majority of these candidate ...

Here, we took advantage of well-defined mouse models for β-amyloidosis (APPPS1) to explore proteome changes in the cerebrospinal fluid which are related to these distinct proteopathic lesions. Non-targeted liquid chromatography-mass spectrometry revealed that the majority of proteins that undergo age- and disease-related changes in either mouse model was linked to microglia, and more specifically to previously described disease state-specific microglia transcriptomic signatures. The finding that ...

Multidimensional single cell-analyses of T cells have fueled the debate about either extensive plasticity or “mixed” priming of T helper cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of T helper cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells ...

The centrosome acts as the cell’s microtubule organizing center, supporting cell division and the extension of cilia and neurites. Newly born neurons require the microtubule organizing activity of centrosomes to migrate away from their birthplace at the ventricle. O’Neill et al. analyzed the centrosome proteome of human induced pluripotent stem cell–derived neural stem cells and neurons. The neural centrosome proteome contains a variety of RNA-binding/modifying proteins, including an RNA-splicing ...