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Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology

2024; Springer Nature; Volume: 15; Issue: 4 Linguagem: Inglês

10.1038/s41419-024-06686-7

2041-4889

Joshua Jackson, Christian Hoffmann, Enzo Scifo, Han Wang, Lena Wischhof, Antonia Piazzesi, Mrityunjoy Mondal, Hanna Shields, Xuesi Zhou, Magali Mondin, Eanna B Ryan, Hermann Döring, Jochen H.M. Prehn, Klemens Rottner, Grégory Giannone, Pierluigi Nicotera, Dan Ehninger, Dragomir Milovanović, Daniele Bano,

Alzheimer's disease research and treatments

Abstract Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson’s disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans . Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.