Targeted Protein Degrader from Ginkgo to Mitigate Amyloid β-Induced Neurotoxicity

Area of Science:

• Biochemistry
• Neuroscience
• Cell Biology

Background:

• Autophagy-lysosome pathway degrades cellular waste, including toxic proteins.
• Amyloid β (Aβ) accumulation causes neurotoxicity and is implicated in Alzheimer's disease (AD).
• A natural product-derived peptide targeting amyloid for autophagy-mediated degradation is currently lacking.

Purpose of the Study:

• To discover and characterize a novel peptide that can induce selective autophagy for amyloid protein degradation.
• To evaluate the therapeutic potential of this peptide against Aβ-induced neurotoxicity.

Main Methods:

• Discovery of β-ginkgotides from Ginkgo biloba nuts.
• Characterization of β-gB1 peptide structure and stability.
• Assessment of cell penetration and neuroprotective effects in an SH-SY5Y neuronal cell model.
• Analysis of Aβ accumulation, gene expression, and autophagy flux.

Main Results:

• β-gB1, a 20-residue peptide with a LC3-interacting region (LIR) motif, was identified.
• β-gB1 demonstrated cell penetration via energy-dependent endocytosis.
• β-gB1 protected against Aβ-induced neurotoxicity, reduced Aβ accumulation, and reversed AD-associated gene expression changes.
• β-gB1 enhanced Aβ aggregate clearance through selective autophagy, maintaining cellular homeostasis.

Conclusions:

• β-ginkgotide represents a first-in-class cysteine-rich peptide (CRP)-based targeted protein degrader.
• β-gB1 shows significant potential as a neuroprotective therapeutic for managing Aβ-induced neurotoxicity in AD and other neurodegenerative disorders.