Cardiolipin-Based Nanoparticles Inhibit α-Synuclein Fibrilization

Synucleinopathies are a group of neurodegenerative disorders characterized by structural aberrations in the protein alpha-synuclein (α-syn). In these disorders, α-syn accumulates and misfolds, contributing to the formation of intracellular inclusion bodies believed to precede cellular death. We investigated the capacity of cardiolipin (CL)-based nanoparticles to reverse α-syn fibrillization, and rescue loss of dopamine neurons. Using circular dichroism (CD) and transmission electron microscopy (TEM), we assessed conformational changes in α-syn upon interaction with CL-nanoparticles. Combined with functional assessment of CL-nanoparticles in rodent models of synucleinopathy, we demonstrate that CL nanoparticles induced structural refolding of fibrillar α-syn toward a monomeric α-helical form, dissolving α-syn aggregates and rescuing from cell death. Thus, CL-based nanoparticles may represent a therapeutic tool to mitigate synucleinopathy.