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Knockdown of endogenous proteins by peptide-directed lysosomal degradation

Rat studies suggest a chaperone-mediated autophagy-targeting motif (CTM) that directs proteins toward lysosomal degradation could provide a method for knockdown of endogenous proteins. Previous cell-based studies showed that CTM-containing fusion proteins are degraded by the lysosome through chaperone-mediated autophagy. In cultured rat cortical neurons, a CTM-tagged, death-associated protein kinase 1 (DAPK1; DAPK)-targeting peptide decreased levels of DAPK1 and oxidative stress-induced damage compared with a CTM-deficient control peptide. In a rat model of focal ischemia, the CTM-tagged, DAPK1-targeting peptide decreased levels of DAPK1 in ischemic brain tissue and ischemic damage compared with the CTM-deficient control peptide. Next steps include developing targeting peptides for disease-causing proteins related to Parkinson's disease (PD), Alzheimer's disease (AD) and cancer.

SciBX 7(9); doi:10.1038/scibx.2014.271
Published online March 6, 2014

Patent application filed by The University of British Columbia; available for licensing

Fan, X. et al. Nat. Neurosci.; published online Jan. 26, 2014;
doi:10.1038/nn.3637
Contact: Yu Tian Wang, The University of British Columbia, Vancouver, British Columbia, Canada
e-mail:

ytwang@brain.ubc.ca