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

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Abnormal alpha-synuclein (α-Syn) accumulation is a hallmark of synucleinopathies like Parkinson's disease (PD).
• α-Syn undergoes liquid-liquid phase separation, forming condensates that can transition into toxic amyloid forms.
• Actin and its regulators are identified as potential interactors of α-Syn.

Purpose of the Study:

• To investigate the role of actin regulators, specifically Neural Wiskott-Aldrich syndrome protein (N-WASP), in α-Syn phase separation and aggregation.
• To understand how N-WASP influences the formation and dynamics of α-Syn inclusions.
• To explore the therapeutic potential of targeting N-WASP in synucleinopathies.

Main Methods:

• Unbiased proteomic analyses to identify α-Syn interactors.
• Cell culture experiments to study N-WASP phase separation and recruitment to α-Syn/synapsin 1 condensates.
• Genetic manipulation in Caenorhabditis elegans (wsp-1/WASL loss of function) to assess α-Syn inclusion dynamics.

Main Results:

• Actin and regulators, including N-WASP, were identified in the α-Syn interactome.
• N-WASP undergoes phase separation and is recruited to synapsin 1 droplets but excluded from α-Syn/synapsin 1 condensates.
• Loss of wsp-1/WASL function in C. elegans altered the number and dynamics of α-Syn inclusions.

Conclusions:

• N-WASP expression may create conditions favoring α-Syn condensate formation.
• N-WASP could play a role in the conversion of α-Syn condensates into toxic species.
• Targeting N-WASP may offer a novel therapeutic strategy for synucleinopathies.