α-Synuclein at the Presynaptic Axon Terminal as a Double-Edged Sword

alpha-synuclein (alpha-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's Disease (AD). In normal physiology, alpha-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise alpha-syn domains interfere with alpha-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the alpha-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of alpha-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective alpha-syn targeted therapy is still plagued by low permeability across the blood-brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain.

Automated summary

alpha-synuclein is a protein strongly associated with the neuropathology observed in Parkinson's disease, dementia with Lewy bodies, and Alzheimer's disease. Mutations and modifications of alpha-syn interfere with its function, leading to abnormalities in presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Targeted therapies for alpha-syn are being explored, and the use of novel encapsulation technology may overcome existing challenges.