%0 Journal Article
%A Jackson, Joshua
%A Hoffmann, Christian
%A Scifo, Enzo
%A Wang, Han
%A Wischhof, Lena
%A Piazzesi, Antonia
%A Mondal, Mrityunjoy
%A Shields, Hanna
%A Zhou, Xuesi
%A Mondin, Magali
%A Ryan, Eanna B
%A Döring, Hermann
%A Prehn, Jochen H M
%A Rottner, Klemens
%A Giannone, Gregory
%A Nicotera, Pierluigi
%A Ehninger, Dan
%A Milovanovic, Dragomir
%A Bano, Daniele
%T Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.
%J Cell death & disease
%V 15
%N 4
%@ 2041-4889
%C London [u.a.]
%I Nature Publishing Group
%M DZNE-2024-00522
%P 304
%D 2024
%X 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.
%K alpha-Synuclein: metabolism
%K Animals
%K Humans
%K Caenorhabditis elegans: metabolism
%K Wiskott-Aldrich Syndrome Protein, Neuronal: metabolism
%K Actins: metabolism
%K Parkinson Disease: metabolism
%K Parkinson Disease: pathology
%K Synapsins: metabolism
%K Caenorhabditis elegans Proteins: metabolism
%K alpha-Synuclein (NLM Chemicals)
%K Wiskott-Aldrich Syndrome Protein, Neuronal (NLM Chemicals)
%K Actins (NLM Chemicals)
%K WASL protein, human (NLM Chemicals)
%K Synapsins (NLM Chemicals)
%K Caenorhabditis elegans Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC11063037
%$ pmid:38693139
%R 10.1038/s41419-024-06686-7
%U https://pub.dzne.de/record/269354