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

Authors:

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, Gregory Giannone, Pierluigi Nicotera, Dan Ehninger, Dragomir Milovanovic, Daniele Bano

Keywords:

alpha-synuclein, Parkinson's, synaptic vesicle condensates, actin, Neural Wiskott-Aldrich syndrome protein, N-WASP, phase separation

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.

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