Anouk Rijs (VU Amsterdam)

Protein aggregation underlies neurodegenerative diseases such as Parkinson's disease and frontotemporal dementia, where intrinsically disordered proteins such as alpha-synuclein misfold and assemble through transient, heterogeneous oligomers en route to amyloid fibrils. These low-abundance, structurally diverse intermediates are considered the most neurotoxic species, yet their transient nature places them beyond the reach of conventional structural techniques. We present a multidimensional advanced mass spectrometry strategy to resolve these elusive assemblies; ion mobility-MS separation maps conformational landscapes of aggregation intermediates, while high-resolution detection extends the accessible range to higher-order oligomers. Our Photo-Synapt platform couples ion mobility with infrared action spectroscopy, delivering vibrational fingerprints that report directly on molecular structure beyond mass and shape. Recent instrumental upgrades extend interrogation times and accessible mass range, enabling measurements on native, patient-derived material. Together, these advances form an integrated platform spanning mass, charge, conformation, and structure, connecting fundamental aggregation mechanisms to disease-relevant biomarker discovery.