Project description
Detecting toxic brain proteins before neurodegenerative symptoms appear
Devastating neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease affect millions of people worldwide. Such conditions are triggered when normally flexible brain proteins cluster into toxic assemblies, damaging neural pathways long before physical symptoms appear. Catching these structural changes early is crucial for effective therapeutic intervention. However, existing diagnostic tools cannot easily isolate these scarce proteins from the human cerebrospinal fluid. Supported by the Marie Skłodowska-Curie Actions programme, the Nanospec project will introduce nanometer-sized glass nanopipettes paired with native mass spectrometry for direct analysis of cerebrospinal fluid. This sensitive platform will improve the resolution of native mass spectrometry readouts by minimising salt adduction to low-abundance toxic proteins to catch structural protein fingerprints at their earliest warning stages.
Objective
Neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD) represent a major global health crisis, with over 9.8 million people in Europe living with dementia. These conditions are driven by intrinsically disordered amyloid proteins, including amyloid-β (Aβ) and α-synuclein (αS), which undergo early conformational changes and aggregate into toxic assemblies. Detecting and characterising these changes at the earliest stages is crucial for timely diagnosis and therapeutic intervention. This fellowship will develop and apply nanopipette-enabled native ion mobility (IM) and top-down mass spectrometry (MS) for the direct analysis of cerebrospinal fluid (CSF), providing the first native MS platform to profile intact proteoforms in complex human biofluids. Nanopipettes are submicron electrospray ionisation emitters that overcome analytical barriers, enabling detection of low-abundance proteins in their native form, mitigating ion suppression and salt adduction. Coupling nanopipette MS with IM and top-down fragmentation will capture conformational ensembles, post translational modifications, and structural fingerprints of disease-associated proteins directly from CSF. Research objectives include: (i) optimising nanopipette workflows with model systems (cell lysates, artificial CSF); (ii) applying these protocols to clinical CSF samples to detect novel disease-specific proteoforms and conformational shifts; and (iii) validating biomarkers using complementary bottom-up proteomics. Collaborative training at UCLA (Prof. Joseph Loo) and VU Amsterdam (Prof. Anouk Rijs) will provide access to cutting-edge Orbitrap, IM-MS, and PhotoSynapt instruments. By pioneering direct native proteoform analysis of CSF, this project addresses an urgent unmet need in biomarker discovery, offering a transformative approach for earlier, more precise AD and PD diagnosis, while establishing a broadly applicable platform for clinical proteomics and next-generation diagnostics.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2025-PF
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1081 HV Amsterdam
Netherlands
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