title: The design and delivery of a PKA inhibitory polypeptide to treat SCA1.
abstract: Spinocerebellar ataxia-1 (SCA1) is a neurodegenerative disease that primarily targets Purkinje cells (PCs) of the cerebellum. The exact mechanism of PC degeneration is unknown, however, it is widely believed that mutant ataxin-1 becomes toxic because of the phosphorylation of its serine 776 (S776) residue by cAMP-dependent protein kinase A (PKA). Therefore, to directly modulate mutant ATXN1 S776 phosphorylation and aggregation, we designed a therapeutic polypeptide to inhibit PKA. This polypeptide comprised of a thermally responsive elastin-like peptide (ELP) carrier, which increases peptide half-life, a PKA inhibitory peptide (PKI), and a cell-penetrating peptide (Synb1). We observed that our therapeutic polypeptide, Synb1-ELP-PKI, inhibited PKA activity at concentrations similar to the PKI peptide. Additionally, Synb1-ELP-PKI significantly suppressed mutant ATXN1 S776 phosphorylation and intranuclear inclusion formation in cell culture. Further, Synb1-ELP-PKI treatment improved SCA1 PC morphology in cerebellar slice cultures. Furthermore, the Synb1-ELP peptide carrier crossed the blood-brain barrier and localized to the cerebellum via the i.p. or intranasal route. Here, we show the intranasal delivery of ELP-based peptides to the brain as a novel delivery strategy. We also demonstrate that our therapeutic polypeptide has a great potential to target the neurotoxic S776 phosphorylation pathway in the SCA1 disease.
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA; Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Scoty M
authors.initials: SM
authors.lastname: Hearst
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Shao
authors.forename: Mariper
authors.initials: M
authors.lastname: Lopez
authors.forename: Drazen
authors.initials: D
authors.lastname: Raucher
authors.forename: Parminder J S
authors.initials: PJ
authors.lastname: Vig
mesh_terms: D000281:Administration, Intranasal; D000595:Amino Acid Sequence; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D020754:Spinocerebellar Ataxias / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D010455:Peptides; D047428:Protein Kinase Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: PKA inhibitory peptide; Purkinje cell; ataxin-1 phosphorylation; intranasal peptide delivery; neurodegeneration; spinocerebellar ataxia-1