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<p>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 Ca<sup>2+</sup>-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.</p>

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Preclinical assessment of a ganglioside-targeted therapy for Parkinson’s disease with the first-in-class adaptive peptide AmyP53

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月17日

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  • Jacques Fantini,
  • Fodil Azzaz,
  • Anaïs Aulas,
  • Henri Chahinian,
  • Nouara Yahi

摘要

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.