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Name of the project- The Role of Lingo1 and BK Channels in tremor   

Brief Description of the Project

Parkinson’s disease is a debilitating disorder characterised by movement disorders, including tremor, cognitive dysfunction and non-motor impairments. It is the second most common age-related neurodegenerative disease with ~10 million sufferers worldwide, but the causes of tremor are poorly understood and treatment is wholly inadequate. This project will use a multidisciplinary approach which marries the expertise of research scientists and clinicians in hospitals, universities and Institutes of Technology to examine how LINGO1 levels in the human brain are associated with tremor in Parkinson’s. We will  aim to identify the cells in which LINGO1 is upregulated, unravel the complex interplay between LINGO1 and ion channels, and detail the precise molecular interactions that lead to the functional knockdown of BK channels by LINGO1. The main impact that this project will have is to enable a pharmacological targeting of LINGO1 for the treatment of Parkinson’s disease and other conditions such as Essential Tremor. Our research will take important steps towards achieving this goal:  We will investigate key biological mechanisms involved in LINGO1’s mechanism of action and BK channel regulation, test first candidates targeting LINGO1, and develop novel pre-clinical models in which drugs targeting LINGO1 can be tested by academic and industrial partners in the future.

Funding from SFI 2023-2026

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Name of the project: Spatiotemporal transcriptome and proteome analysis of α-Synuclein pathology in Parkinson’s disease: Identification of cell type-specific vulnerability and tolerance mechanisms (4DPD-Omics­)

Brief description of the project

Parkinson’s disease (PD), yet we have very limited understanding why specific neuronal populations are vulnerable to α-Syn-related PD pathology while others are much more resistant. Likewise, we have very limited knowledge of whether neurons may transition from a resistant state to a vulnerable state, how neuronal vulnerability manifests itself during disease development, how it defines distinct stages of α-Syn pathology, and how other non-neuronal cells (astroglia, microglia, infiltrating immune cells) contribute to these processes. 4DPD-Omics is a consortium of experts in α-Syn biochemistry, neuroanatomy and neuropathology, translational α-Syn disease models, spatial and single cell omics profiling, bioinformatics and systems biology who are ideally positioned to perform an unprecedented, integrated, spatiotemporal transcriptome and proteome analysis of neuronal and non-neuronal responses to α-Syn pathology. The consortium has already collaboratively generated rich sets of bulk transcriptomics and proteomics data in preclinical models and post mortem human samples with α-Syn pathology. Using these data and subsequent bioinformatics and functional interrogations, the 4DPD-Omics consortium members have identified mitochondrial dysfunction, rewiring of metabolic networks, defects in mitophagy/autophagy, proinflammatory processes and altered synaptic vesicle trafficking as key mechanisms contributing to α-Syn pathology. However, it remains unresolved which cell types display these changes, how these processes are altered over time in the context of development and spreading of targeted α-Syn pathology and neurodegeneration, and which signalling pathways trigger these alterations. 4DPD-Omics will avail of well characterised preclinical mouse models developed by consortium partners (striatal injections of α-Syn fibrils with progressive disease-like pathology), as well as clinically and genetically annotated human post mortem samples of defined Braak stages (0-VI), to perform an in-depth cell-specific spatial transcriptomics and proteomics analysis. We will avail of spatial transcriptomics, mass spectrometry, and CellDIVE multiplexing platforms to determine whole transcriptome/proteome changes at spatial tissue level and single cell level in neuronal and non-neuronal cell populations over time, and correlate these alterations to the progression and spreading of α-Syn pathology.

  *   Principal Investigator/Researchers: Prof Jochen Prehn, Prof Donato Di Monte, Dr Ronald Melki, Prof Wilma van de Berg, Dr Niamh Connolly, Dr György Vámosi, Masja van het Hoofd, Prof Mauno Vihinen

  *   Disease Area: Parkinson’s Disease

  *   Field of Research: Neurodegeneration

  *   Institution Royal College of Surgeons In Ireland (Co-ordinator)

Partners Institutes include: DZNE, Germany; CNRS/CEA, France; Vrije University Amsterdam, Netherlands;  Lund University, Sweeden ; University of Debrecen, Hungary.

Start year 2023-2026

Funding body- JPND-HRB