DOI: 10.1038/s41598-025-94148-1
We propose a new concept for the treatment of Parkinson’s disease (PD), which considers that its root cause, α-synuclein, is an intrinsically disordered protein (IDP) difficult to target by classic approaches. Upon binding to lipid raft gangliosides, α-synuclein shifts from random coil to α-helix, forming Ca2+-permeable oligomeric pores triggering a neurotoxicity cascade. We used the α-synuclein-ganglioside interaction as guideline to design a therapeutic peptide (AmyP53) that combines the respective flexible ganglioside-binding domains of α-synuclein and Alzheimer’s β-amyloid protein. AmyP53 is an adaptive peptide, the first representant of a new therapeutic class. It acts as a competitive inhibitor of α-synuclein oligomer formation in brain cell membranes and prevents subsequent downstream synaptotoxicity, including the loss of dopaminergic neurons in an animal α-synuclein injection model of PD. It is active against both wild-type and mutant forms of α-synuclein. AmyP53 is administered intranasally without side effects. This new concept “target the target (gangliosides), not the arrow (IDP)” is distinct from classic α-synuclein centric approaches that did not cure PD so far.
