Title of Project
- Spatiotemporal transcriptome and proteome analysis of α-Synuclein pathology in Parkinson’s disease: Identification of cell type-specific vulnerability and tolerance mechanisms ( JPND 4DPD Omics-)
| Consortium | Affiliation and E-mail | |
| Coordinator | Prof Jochen Prehn | Royal College of Surgeons in Ireland, University. Physiology & Medical Physics Royal College of Surgeons in Ireland 123 St. Stephens Green, Dublin 2, IRELAND. Tel. 00-353-1-4022261 E-mail: prehn@rcsi.ie |
| Partner 2: | Prof Donato Di Monte | DZNE-Germany E-mail: Donato.DiMonte@dzne.de |
| Partner 3: | Dr Ronald Melki | CNRS/CEA- France E-mail: ronald.melki@cea.fr |
| Partner 4: | Prof Wilma van de Berg | Amsterdam UMC, Vrije University Amsterdam, University Hospital. E-mail: wdj.vandeberg@amsterdamumc.nl |
| Partner 5: | Prof Mauno Vihinen | Lund University- Sweden E-mail: mauno.vihinen@med.lu.se |
| Partner 6: | Dr Niamh Connolly | Royal College of Surgeons in Ireland E-mail: niamhmconnolly@rcsi.ie |
| Partner 7: | Dr György Vámosi | Faculty of Medicine, University of Debrecen E-mail: vamosig@med.unideb.hu |
| Partner 8: | Prof Zbyněk Zdráhal | CEITEC Masaryk University E-mail: zdrahal@sci.muni.cz |
| External Collaborators | ||
| Masja van het Hoofd, Parkinson Vereniging (Patient association)- Netherlands | ||
Background to the Project:
α-Synuclein (α-Syn) pathology is inextricably linked to the pathogenesis of 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. We will create a 4D dynamic atlas of the distribution of specific cell subpopulations, correlate their transcriptome/proteome changes to their vulnerability to pathogenic processes, and characterise the spatial cellular landscape in relation to α-Syn pathology. Integrative bioinformatics analyses, including network modelling and master regulator analyses, will identify biomarkers, pathways, and signatures in cellular sub-types susceptible and resistant to α-Syn pathology that may precede appearance of the pathological phenotype. Utilising systems biology approaches such as genome scale modelling, previously identified disease pathways will be systematically investigated in the context of disease progression and the cell types in which they occur, and mapped to master regulators. Identified signalling pathways and master regulators will be validated in clinical samples using multiplexing approaches that enable the quantification of up to 50 markers in ±10,000 individual cells within a single tissue section/region, providing unprecedented insights into disease patterns in humans at single cell resolution. Collectively, by generating spatial tissue profiles and more than 10,000,000 single cell profiles and by analysing the spatiotemporal responses of vulnerable and less vulnerable neurons and non-neuronal cells to α-Syn pathology, we will identify biomarkers of disease progression and endophenotypes in PD patients, representing novel cell-specific targets and strategies for drug development.
Disease Area:
Parkinson’s disease.
Field of Research:
Neuroscience, Molecular Biology, Parkinson’s Disease Research, Proteomics, Transcriptomics.
Institution:
This is a joint research project between RCSI and six other European partners/institutions. Please refer to the table above for more details.
Funding: For RCSI, the funding agency is HRB
2) Name of the project: LINGO1 a novel regulatory subunit of BK channels implicated in tremor.
* Brief description of the project (as long or as short as you’d like):
Parkinson’s disease is a debilitating disorder characterized by uncontrolled limb shaking (tremor), slow movement, dementia and depression. It is the second most common age-related neurodegenerative disease affecting ~10 million worldwide, yet the causes of tremor are poorly understood and treatment is wholly inadequate. Tremor is linked to proteins called ion channels. These tiny molecular pores are studded into the cell membrane, permit the flow of ions through it and help to control nerves. This project will determine how a protein called LINGO1 affects ion channels and causes tremor, and whether drugs can be developed to relieve the symptoms of tremor
* Principal Investigator/Researchers: Prof Jochen Prehn/ Fred J. Edzeamey
* Disease Area: Parkinson’s Disease and Tremor
* Field of Research: Neuroscience and Neurology
* Institution: Royal College of Surgeons in Ireland
* Start year: 2024
* Projected Completed: (either yes/no or projected finish date): No
* Funding body: SFI
* Recruiting Research Participants yes/no and if yes, further information and contact details
3) Harnessing the therapeutic potential of FKBPL in Parkinson’s Disease
* Brief description of the project (as long or as short as you’d like)
Parkinson’s Disease (PD) is the second most frequent, degenerative neurological condition affecting up to ten million worldwide and occurs through loss of dopamine-producing neurons. PD etiology/pathogenesis remain incompletely understood, however, mitochondrial dysfunction, protein aggregation and neuroinflammation play a role in PD development. FK506 binding proteins (FKBP) belong to the highly conserved immunophilin superfamily of proteins with fundamental roles in protein folding/receptor signaling/protein trafficking/molecular chaperone activity. Several members of the FKBP family are promising therapeutic targets including in neurodegeneration.
Robson/Annett have extensively characterized a divergent member of this family, FK506 binding like protein (FKBPL), in cancer/inflammatory disease via regulation of angiogenesis, stem cell differentiation, and NF-kappa-β-associated inflammation. Here we aim to explore a new therapeutic indication for this protein in PD as new FKBPL biology has arisen. FKBPL binds to and induces degradation of dual leucine zipper kinase (DLK). DLK is highly expressed in the nervous system and, of note, DLK strongly regulates neurodegeneration in PD by JNK activation. We therefore predict that FKBPL-based therapeutics could induce DLK degradation, inhibiting JNK, leading to neuroprotection; in addition to FKBPL’s anti-neuroinflammatory action, inhibiting innate immune signalling induced by alpha-synuclein aggregates.
* Principal Investigator/Researchers: Stephanie Annett, Tracy Robson, Jochen Prehn, Niamh Connolly
* Disease Area: Parkinson’s Disease
* Field of Research: Neurodegeneration, Therapeutics; Neuropharmacolgy – please assign what you think is most appropriate
* Institution RCSI
* Start year Q1 2025
* Projected Completed: (either yes/no or projected finish date): No – funding starting Q1 2025
* Funding body: SFI
* Recruiting Research Participants yes/no and if yes, further information and contact details: No
4) AIPD – AI In Parkinson’s Disease
* Brief description of the project (as long or as short as you’d like):
AI in Parkinson’s Disease (AIPD) is a Marie Skłodowska-Curie Joint Industry-Academic Doctoral Network. AIPD will train a group of 14 Doctoral Candidates in an intersectoral, international and interdisciplinary setting with the aim to educate the next generation of medical data scientists. Our program stands out by a strong translational focus bridging academia and industry. PhD candidates will benefit from:
- Networking Opportunities: AIPD enhances collaboration with leading institutions and researchers in academia and industry across Europe.
- Training and Skills Development: AIPD offers comprehensive training in research and transferable skills, contributing to professional growth.
- Career Advancement: AIPD increases the employability and career prospects of researchers through high-quality research experiences.
- Innovation and Impact: AIPD drives innovation and contributes to societal challenges by supporting cutting-edge research projects in the intersection field of AI and biomedicine.
- Recognition and Prestige: Affiliation with a Marie Skłodowska-Curie program is highly regarded, adding significant value to the researchers’ profiles.
AIPD’s competitive research program covers areas of highest interest for science and society with applications to Parkinson’s Disease:
· Precision medicine
· Digital health
· Trustworthy AI
* Principal Investigator/Researchers Niamh Connolly, Jochen Prehn
* Disease Area Parkinson’s Disease
* Field of Research AI
* Institution RCSI University in Medicine & Health Sciences
* Start year 2024 (PhD students to begin in 2025)
* Projected Completed: (either yes/no or projected finish date) 2028
* Funding body MSCA
* Recruiting Research Participants yes/no and if yes, further information and contact details Yes. Find out more about AIPD at https://www.aipd-dn.eu. As part of AIPD, RCSI are recruiting 2 PhD students (mobility rules apply, apply by Feb 28th 2025): “Metabolic Blood Biomarkers for Personalised Disease Monitoring” (https://euraxess.ec.europa.eu/jobs/290650) and “Identification of Molecular PD Endophenotypes” (https://euraxess.ec.europa.eu/jobs/290899)
5) Development of Novel Oligogenic ALS Models for Drug Discovery
* Brief description of the project (as long or as short as you’d like)
Amyotrophic Lateral Sclerosis (ALS) is a fatal disease resulting in muscle weakness, paralysis and ultimately death, often within 2-3 years of symptom onset. These symptoms arise due to the loss of motor neurons from the brain and spinal cord. Treatment options are limited and have little impact on halting progression of the disease. This research project is aimed at developing and characterising new models of ALS that can be used to investigate how motor neurons degenerate in people living with ALS. We expect that this project will provide a foundation to highlight new drug targets for exploitation in future research.
* Principal Investigator/Researchers
PI: Prof. Jochen Prehn
* Disease Area
Amyotrophic Lateral Sclerosis/Motor Neuron Disease
* Field of Research
Neurodegeneration
* Institution
Royal College of Surgeons in Ireland
* Start year
2022
* Projected Completed: (either yes/no or projected finish date)
No, projected finish date 2025
* Funding body
This research is supported in part by a research grant from Taighde Éireann – Research Ireland under Grant Number 21/RC/10294_P2 and co-funded under the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 101034252
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