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91 Publications visible to you, out of a total of 91
C9orf72 protein quality control by UBR5-mediated heterotypic ubiquitin chains.

Abstract (Expand)

Hexanucleotide repeat expansions within C9orf72 are a frequent cause of amyotrophic lateral sclerosis and frontotemporal dementia. Haploinsufficiency leading to reduced C9orf72 protein contributes to … disease pathogenesis. C9orf72 binds SMCR8 to form a robust complex that regulates small GTPases, lysosomal integrity, and autophagy. In contrast to this functional understanding, we know far less about the assembly and turnover of the C9orf72-SMCR8 complex. Loss of either subunit causes the concurrent ablation of the respective partner. However, the molecular mechanism underlying this interdependence remains elusive. Here, we identify C9orf72 as a substrate of branched ubiquitin chain-dependent protein quality control. We find that SMCR8 prevents C9orf72 from rapid degradation by the proteasome. Mass spectrometry and biochemical analyses reveal the E3 ligase UBR5 and the BAG6 chaperone complex as C9orf72-interacting proteins, which are components of the machinery that modifies proteins with K11/K48-linked heterotypic ubiquitin chains. Depletion of UBR5 results in reduced K11/K48 ubiquitination and increased C9orf72 when SMCR8 is absent. Our data provide novel insights into C9orf72 regulation with potential implication for strategies to antagonize C9orf72 loss during disease progression.

Authors: J. Julg, D. Edbauer, C. Behrends

Date Published: 3rd Aug 2023

Publication Type: Journal

Spatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury.

Abstract (Expand)

Understanding the complexity of cellular function within a tissue necessitates the combination of multiple phenotypic readouts. Here, we developed a method that links spatially-resolved gene expression … of single cells with their ultrastructural morphology by integrating multiplexed error-robust fluorescence in situ hybridization (MERFISH) and large area volume electron microscopy (EM) on adjacent tissue sections. Using this method, we characterized in situ ultrastructural and transcriptional responses of glial cells and infiltrating T-cells after demyelinating brain injury in male mice. We identified a population of lipid-loaded "foamy" microglia located in the center of remyelinating lesion, as well as rare interferon-responsive microglia, oligodendrocytes, and astrocytes that co-localized with T-cells. We validated our findings using immunocytochemistry and lipid staining-coupled single-cell RNA sequencing. Finally, by integrating these datasets, we detected correlations between full-transcriptome gene expression and ultrastructural features of microglia. Our results offer an integrative view of the spatial, ultrastructural, and transcriptional reorganization of single cells after demyelinating brain injury.

Authors: P. Androvic, M. Schifferer, K. Perez Anderson, L. Cantuti-Castelvetri, H. Jiang, H. Ji, L. Liu, G. Gouna, S. A. Berghoff, S. Besson-Girard, J. Knoferle, M. Simons, O. Gokce

Date Published: 11th Jul 2023

Publication Type: Journal

The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.

Abstract (Expand)

BACKGROUND: The protease BACE1 is a major drug target for Alzheimer's disease, but chronic BACE1 inhibition is associated with non-progressive cognitive worsening that may be caused by modulation … of unknown physiological BACE1 substrates. METHODS: To identify in vivo-relevant BACE1 substrates, we applied pharmacoproteomics to non-human-primate cerebrospinal fluid (CSF) after acute treatment with BACE inhibitors. RESULTS: Besides SEZ6, the strongest, dose-dependent reduction was observed for the pro-inflammatory cytokine receptor gp130/IL6ST, which we establish as an in vivo BACE1 substrate. Gp130 was also reduced in human CSF from a clinical trial with a BACE inhibitor and in plasma of BACE1-deficient mice. Mechanistically, we demonstrate that BACE1 directly cleaves gp130, thereby attenuating membrane-bound gp130 and increasing soluble gp130 abundance and controlling gp130 function in neuronal IL-6 signaling and neuronal survival upon growth-factor withdrawal. CONCLUSION: BACE1 is a new modulator of gp130 function. The BACE1-cleaved, soluble gp130 may serve as a pharmacodynamic BACE1 activity marker to reduce the occurrence of side effects of chronic BACE1 inhibition in humans.

Authors: S. A. Muller, M. D. Shmueli, X. Feng, J. Tushaus, N. Schumacher, R. Clark, B. E. Smith, A. Chi, S. Rose-John, M. E. Kennedy, S. F. Lichtenthaler

Date Published: 21st Feb 2023

Publication Type: Journal

Spatial proteomics reveals secretory pathway disturbances caused by neuropathy-associated TECPR2.

Abstract (Expand)

Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare fatal neurological disease caused by mis- and nonsense mutations in the gene encoding for Tectonin beta-propeller repeat containing protein … 2 (TECPR2). While TECPR2 is required for lysosomal consumption of autophagosomes and ER-to-Golgi transport, it remains elusive how exactly TECPR2 is involved in autophagy and secretion and what downstream sequels arise from defective TECPR2 due to its involvement in these processes. To address these questions, we determine molecular consequences of TECPR2 deficiency along the secretory pathway. By employing spatial proteomics, we describe pronounced changes with numerous proteins important for neuronal function being affected in their intracellular transport. Moreover, we provide evidence that TECPR2's interaction with the early secretory pathway is not restricted to COPII carriers. Collectively, our systematic profiling of a HSAN9 cell model points to specific trafficking and sorting defects which might precede autophagy dysfunction upon TECPR2 deficiency.

Authors: K. Nalbach, M. Schifferer, D. Bhattacharya, H. Ho-Xuan, W. C. Tseng, L. A. Williams, A. Stolz, S. F. Lichtenthaler, Z. Elazar, C. Behrends

Date Published: 16th Feb 2023

Publication Type: Journal

Met/HGFR triggers detrimental reactive microglia in TBI.

Abstract (Expand)

The complexity of signaling events and cellular responses unfolding in neuronal, glial, and immune cells upon traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links … and targets for intervention. We use array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then scrutinize the large-scale effects of perturbation of Met/HGFR, VEGFR1, and Btk signaling by small molecules. We show Met/HGFR as a selective modifier of early microglial response and that Met/HGFR blockade prevents the induction of microglial inflammatory mediators, of reactive microglia morphology, and TBI-associated responses in neurons and vasculature. Both acute and prolonged Met/HGFR inhibition ameliorate neuronal survival and motor recovery. Early elevation of HGF itself in the cerebrospinal fluid of TBI patients suggests that this mechanism has translational value in human subjects. Our findings identify Met/HGFR as a modulator of early neuroinflammation in TBI with promising translational potential.

Authors: Rida Rehman, Michael Miller, Sruthi Sankari Krishnamurthy, Jacob Kjell, Lobna Elsayed, Stefanie M Hauck, Florian Olde Heuvel, Alison Conquest, Akila Chandrasekar, Albert Ludolph, Tobias Boeckers, Medhanie A Mulaw, Maria Cristina Morganti-Kossmann, Aya Takeoka, Francesco Roselli, Magdalena Götz

Date Published: 27th Dec 2022

Publication Type: Journal

Beneficial Effect of ACI-24 Vaccination on Abeta Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse Model.

Abstract (Expand)

Amyloid-beta (Abeta) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Abeta plaques, but their phagocytic capacity … declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Abeta targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Abeta plaque load, Abeta plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Abeta plaques, we observed a more ramified morphology of Abeta plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Abeta plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Abeta targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.

Authors: J. Rudan Njavro, M. Vukicevic, E. Fiorini, L. Dinkel, S. A. Muller, A. Berghofer, C. Bordier, S. Kozlov, A. Halle, K. Buschmann, A. Capell, C. Giudici, M. Willem, R. Feederle, S. F. Lichtenthaler, C. Babolin, P. Montanari, A. Pfeifer, M. Kosco-Vilbois, S. Tahirovic

Date Published: 24th Dec 2022

Publication Type: Journal

Spatial proteomics in three-dimensional intact specimens.

Abstract (Expand)

Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of large biological specimens … imaged in 3D are lacking. Here, we present DISCO-MS, a technology that combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry. DISCO-MS yielded proteome data indistinguishable from uncleared samples in both rodent and human tissues. We used DISCO-MS to investigate microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer's disease. DISCO-bot robotic sample extraction enabled us to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. DISCO-MS enables unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D, identifying diagnostic and therapeutic opportunities for complex diseases. VIDEO ABSTRACT.

Authors: H. S. Bhatia, A. D. Brunner, F. Ozturk, S. Kapoor, Z. Rong, H. Mai, M. Thielert, M. Ali, R. Al-Maskari, J. C. Paetzold, F. Kofler, M. I. Todorov, M. Molbay, Z. I. Kolabas, M. Negwer, L. Hoeher, H. Steinke, A. Dima, B. Gupta, D. Kaltenecker, O. S. Caliskan, D. Brandt, N. Krahmer, S. Muller, S. F. Lichtenthaler, F. Hellal, I. Bechmann, B. Menze, F. Theis, M. Mann, A. Erturk

Date Published: 22nd Dec 2022

Publication Type: Journal

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