Journal Article

DZNE-2024-00522

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.

Jackson, J. (First author)DZNE* ; Hoffmann, C. (First author)DZNE* ; Scifo, E.DZNE* ; Wang, H.DZNE* ; Wischhof, L.DZNE* ; Piazzesi, A. ; Mondal, M.DZNE* ; Shields, H.DZNE* ; Zhou, X. ; Mondin, M. ; Ryan, E. B. ; Döring, H. ; Prehn, J. H. M. ; Rottner, K. ; Giannone, G. ; Nicotera, P.DZNE* ; Ehninger, D.DZNE* ; Milovanovic, D.DZNE* ; Bano, D. (Last author)DZNE*

2024
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41419-024-06686-7

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.

Keyword(s): alpha-Synuclein: metabolism (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Caenorhabditis elegans: metabolism (MeSH) ; Wiskott-Aldrich Syndrome Protein, Neuronal: metabolism (MeSH) ; Actins: metabolism (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Parkinson Disease: pathology (MeSH) ; Synapsins: metabolism (MeSH) ; Caenorhabditis elegans Proteins: metabolism (MeSH) ; alpha-Synuclein ; Wiskott-Aldrich Syndrome Protein, Neuronal ; Actins ; WASL protein, human ; Synapsins ; Caenorhabditis elegans Proteins

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Contributing Institute(s):

1. Aging and Neurodegeneration (AG Bano)
2. Molecular Neuroscience (AG Milovanovic)
3. Translational Biogerontology (AG Ehninger)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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