Siebourg-Polster, J. | Search bioRxiv

bioRxiv2023

Kinex infers causal kinases from phosphoproteomics data

MotivationPhosphoproteomics data are essential for characterising signalling pathways, identifying drug targets, and evaluating efficacy and safety profiles of drug candidates. Emerging resources, including a substrate-specificity atlas and drug-induced phosphoproteomics profiles, may transform the inference of causal kinases. However, there is currently no open-source software that leverages insights derived from these resources. ResultsWe introduce Kinex, a workflow implemented in the same-name Python package, which infers causal serine/threonine kinases from phosphoproteomics data. Kinex allows users to score kinase-substrate interactions, perform enrichment analysis, visualise candidates of causal regulators, and query similar profiles in a database of drug-induced kinase activities. Analysing seven published studies and one newly generated dataset, we demonstrate that analysis with Kinex recovers causal effects of perturbations and reveals novel biological insights. We foresee that Kinex will become an indispensable tool for basic and translational research including drug discovery. AvailabilityKinex is released with the GNU General Public License and available at https://github.com/bedapub/kinex.

bioinformatics↗

bioRxiv2018

Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

Intraneuronal accumulation of -synuclein (Syn) is key in the pathogenesis of Parkinsons disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of Syn remain unknown but evidence is growing, that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit Syn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger Syn accumulation in the ENS of wildtype and Syn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of Syn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 Syn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old Syn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.

neuroscience↗