Aggregate Deep Visual Proteomics reveals selective organization of α-synuclein inclusions

Aggregate Deep Visual Proteomics shows that α-synuclein inclusions in HEK293 cells, iPSC-derived dopaminergic neurons, and post-mortem patient brain selectively concentrate a subset of the host proteome, including V-ATPase in all three systems.

• Why it matters: Inclusion composition is linked to neuron dysfunction and degeneration, but prior interpretations (protective deposits, toxic species, or failed degradation products) require knowing what inclusions enrich relative to their originating cell.
• What they did: The method profiles laser-microdissected inclusions versus the remainder of the same cell or a matched host using ultrasensitive mass spectrometry, including complex-level tracking where subunits move together in 421 of 438 complexes.
• The result: Inclusions enrich membrane-associated proteins largely presynaptically in neurons, keep degradation cargo with its routing receptors, and differ by inclusion type (neuritic vs somatic), enabling inclusion composition as a readout of formation and candidate markers.

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