TY  - JOUR
AU  - Jackson, Joshua
AU  - Hoffmann, Christian
AU  - Scifo, Enzo
AU  - Wang, Han
AU  - Wischhof, Lena
AU  - Piazzesi, Antonia
AU  - Mondal, Mrityunjoy
AU  - Shields, Hanna
AU  - Zhou, Xuesi
AU  - Mondin, Magali
AU  - Ryan, Eanna B
AU  - Döring, Hermann
AU  - Prehn, Jochen H M
AU  - Rottner, Klemens
AU  - Giannone, Gregory
AU  - Nicotera, Pierluigi
AU  - Ehninger, Dan
AU  - Milovanovic, Dragomir
AU  - Bano, Daniele
TI  - Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.
JO  - Cell death & disease
VL  - 15
IS  - 4
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2024-00522
SP  - 304
PY  - 2024
AB  - 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.
KW  - alpha-Synuclein: metabolism
KW  - Animals
KW  - Humans
KW  - Caenorhabditis elegans: metabolism
KW  - Wiskott-Aldrich Syndrome Protein, Neuronal: metabolism
KW  - Actins: metabolism
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Synapsins: metabolism
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - alpha-Synuclein (NLM Chemicals)
KW  - Wiskott-Aldrich Syndrome Protein, Neuronal (NLM Chemicals)
KW  - Actins (NLM Chemicals)
KW  - WASL protein, human (NLM Chemicals)
KW  - Synapsins (NLM Chemicals)
KW  - Caenorhabditis elegans Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11063037
C6  - pmid:38693139
DO  - DOI:10.1038/s41419-024-06686-7
UR  - https://pub.dzne.de/record/269354
ER  -