proteomics

NOTE: DUE TO A CYBER ATTACK OUR UNIVERSITY WEB SYSTEM IS SHUT DOWN - TALK WILL BE RESCHEDULED

The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output and how neurons are integrated in the surrounding neuronal network. Accordingly, neurons with aberrant morphology have been associated with neurological disorders. Dysmorphic, enlarged neurons are, for example, a hallmark of focal epileptogenic lesions like focal cortical dysplasia (FCDIIb) and gangliogliomas (GG). However, the regulatory mechanisms governing the development of dendrites are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. Nevertheless, its function in neurons is unknown. We found that during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, ≥ 3rd, order dendrites both in cultured neurons and living mice. Moreover, SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown causes a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, while excitatory neurotransmission is unaffected. This mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations exhibit significant loss of SLK expression. To uncover the signaling cascades underlying the action of SLK, we combined phosphoproteomics, protein interaction screens and single cell RNA seq. Overall, our data identifies SLK as a key regulator of both dendritic complexity during development and of inhibitory synapse maintenance.

Towards a More Authentic Vision of the (multi)Coding Potential of RNA

Ten of thousands of open reading frames (ORFs) are hidden within transcripts. They have eluded annotations because they are either small or within unsuspected locations. These are named alternative ORFs (altORFs) or small ORFs and have recently been highlighted by innovative proteogenomic approaches, such as our OpenProt resource, revealing their existence and implications in biological functions. Due to the absence of altORFs from annotations, pathogenic mutations within these are being ignored. I will discuss our latest progress on the re-analysis of large-scale proteomics datasets to improve our knowledge of proteomic diversity, and the functional characterization of a second protein coded by the FUS gene. Finally, I will explain the need to map the coding potential of the transcriptome using artificial intelligence rather than with conventional annotations that do not capture the full translational activity of ribosomes.

Advances and setbacks in prion biology

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species caused by prions. The main constituent of prions is PrPSc, an aggregated moiety of the host-derived membrane glycolipoprotein PrPC. Prions were found to encipher many phenotypic, genetically stable TSE variants. The latter is very surprising, since PrPC is encoded by the host genome and all prion strains share the same amino acid sequence. Here I will review what is known about the infectivity, the neurotoxicity, and the neuroinvasiveness of prions. Also, I will explain why I regard the prion strain question as a fascinating challenge – with implications that go well beyond prion science. Finally, I will report some recent results obtained in my laboratory, which is attempting to address the strain question and some other basic issues of prion biology with a “systems” approach that utilizes organic chemistry, photophysics, proteomics, and mouse transgenesis.

Targeting the synapse in Alzheimer’s Disease

Alzheimer’s Disease is characterised by the accumulation of misfolded proteins, namely amyloid and tau, however it is synapse loss which leads to the cognitive impairments associated with the disease. Many studies have focussed on single time points to determine the effects of pathology on synapses however this does not inform on the plasticity of the synapses, that is how they behave in vivo as the pathology progresses. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of tauopathy[1] (rTg4510) and amyloidopathy[2] (J20). This revealed that pre- and post-synaptic components are differentially affected in both AD models in response to pathology. In the Tg4510 model, differences in the stability and turnover of axonal boutons and dendritic spines immediately prior to neurite degeneration was revealed. Moreover, the dystrophic neurites could be partially rescued by transgene suppression. Understanding the imbalance in the response of pre- and post-synaptic components is crucial for drug discovery studies targeting the synapse in Alzheimer’s Disease. To investigate how sub-types of synapses are affected in human tissue, the Multi-‘omics Atlas Project, a UKDRI initiative to comprehensively map the pathology in human AD, will determine the synaptome changes using imaging and synaptic proteomics in human post mortem AD tissue. The use of multiple brain regions and multiple stages of disease will enable a pseudotemporal profile of pathology and the associated synapse alterations to be determined. These data will be compared to data from preclinical models to determine the functional implications of the human findings, to better inform preclinical drug discovery studies and to develop a therapeutic strategy to target synapses in Alzheimer’s Disease[3].

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FENS Forum 2024