Penetratin inhibits α-synuclein fibrillation and improves locomotor functions in mice model of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The presence of lewy bodies, primarily consisting of α-synuclein (α-syn) aggregates is one of the common features seen in the substantia nigra region of the brain in PD patients. The disease remains incurable and only symptomatic relief is available. We screened various cell-penetrating peptides and reveal that penetratin is a potent inhibitor of α-syn aggregation in-vitro, and significantly improved locomotor coordination in mice models of PD in-vivo. The peptide inhibits α-syn aggregation in vitro as well as in yeast, and C.elegans models. We further made a cyclic derivative of penetratin by disulfide coupling of N- and C-terminal cysteine residues. Both penetratin and its cyclized derivative interact with α-syn. NMR studies show that both linear as well as cyclic derivative interact at the acidic C-terminal tail of the protein. Similar to penetratin, its cyclic derivative inhibited α-syn aggregation in the C.elegans model of Parkinson’s disease, and also improved worm motility. Molecular Dynamics studies show that penetratin interacts with α-synuclein and prevents its conformational transition from disordered into β-sheet rich structure. The therapeutic efficacy of penetratin was further confirmed in a transgenic mice model of the disease, wherein penetratin treatment over a period of 90 days improved locomotor coordination, and halted disease progression. Overall, the present work provides a potent therapeutic agent that could be further explored in the management of PD.

Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases

“…In a transgenic mice model of the disease, treatment with Pen over a period of 90 days improved motor coordination and halted disease progression. Thus, the peptides have the potential to improve overall dopamine health and heal the effects associated with aggregation …”

“…Thus, the peptides have the potential to improve overall dopamine health and heal the effects associated with aggregation. 19 An N-terminally truncated derivative of Pen turns out to be a nonaggregating peptide that exhibits a 12-fold higher binding affinity to oligomeric α-Syn species (αSOs) than to α-Syn monomer. αSOs are formed at early stages of aggregation and are responsible for cytotoxicity.…”

“…18 Penetratin also inhibits α-Syn fibrillation and blocks clinical symptoms in PD mouse models, while a cyclic derivative of penetratin shows potent inhibition of α-Syn aggregation in vitro and in vivo in Caenorhabditis elegans models of PD. 19 Here, we discuss how CPPs alone or with nanomaterials can act as therapeutics for CNS disorders and as amyloid inhibitors in AD and PD. This work highlights the application of CPPs in CNS diseases, particularly AD and PD, unlike other reviews on CPPs/CPP-cargo.…”

“…A promising nonaggregating peptide (p216) derived from the CPP penetratin has the potential to target toxic α-Syn oligomers in Parkinson’s disease . Penetratin also inhibits α-Syn fibrillation and blocks clinical symptoms in PD mouse models, while a cyclic derivative of penetratin shows potent inhibition of α-Syn aggregation in vitro and in vivo in Caenorhabditis elegans models of PD …”

A penetratin-derived peptide reduces the membrane permeabilization and cell toxicity of α-synuclein oligomers

“…One of the most widely used CPPs is pAntp ( 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ) (also known as penetratin, sequence RQIKIWFQNRRMKWKK), which derives from the third helix of the Antennapedia protein homeodomain ( 57 , 63 ). Penetratin has been shown to inhibit fibrillation of α-syn ( 64 ), making it a promising starting point for peptides able to bind specifically to αSOs.…”