A DJ-1 Based Peptide Attenuates Dopaminergic Degeneration in Mice Models of Parkinson's Disease via Enhancing Nrf2

Abstract

Drugs currently used for treating Parkinson's disease patients provide symptomatic relief without altering the neurodegenerative process. Our aim was to examine the possibility of using DJ-1 (PARK7), as a novel therapeutic target for Parkinson's disease. We designed a short peptide, named ND-13. This peptide consists of a 13 amino acids segment of the DJ-1-protein attached to 7 amino acids derived from TAT, a cell penetrating protein. We examined the effects of ND-13 using in vitro and in vivo experimental models of Parkinson's disease. We demonstrated that ND-13 protects cultured cells against oxidative and neurotoxic insults, reduced reactive oxygen species accumulation, activated the protective erythroid-2 related factor 2 system and increased cell survival. ND-13 robustly attenuated dopaminergic system dysfunction and in improved the behavioral outcome in the 6-hydroxydopamine mouse model of Parkinson's disease, both in wild type and in DJ-1 knockout mice. Moreover, ND-13 restored dopamine content in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model. These findings validate DJ-1 as a promising therapeutic target in Parkinson's disease and identify a novel peptide with clinical potential, which may be significant for a broader range of neurological diseases, possibly with an important impact for the neurosciences.

Nrf2: a modulator of Parkinson’s disease?

“…Recently, a short, cell penetrating, peptide derivative of DJ-1 was shown to attenuate H2O2, 6-OHDA, and DA induced oxidative stress in neuroblastoma cell lines (Lev, Barhum et al 2015).…”

ND-13, a DJ-1-Derived Peptide, Attenuates the Renal Expression of Fibrotic and Inflammatory Markers Associated with Unilateral Ureter Obstruction

“…Dr. Daniel Offen’s laboratory, at the University of Tel Aviv, developed a 13 aa-long peptide derived from the most conserved sequence of DJ-1 [ 23 ]. To achieve cell permeability, this 13 aa chain was fused to a 7 aa TAT sequence (YGRKKRR).…”

“…To achieve cell permeability, this 13 aa chain was fused to a 7 aa TAT sequence (YGRKKRR). The resulting 20 amino acid compound was named ND-13 and was demonstrated to be effective in protecting neuronal cultures from the effects of relevant neurotoxins in the setting of Parkinson’s disease, amyotrophic lateral sclerosis or multiple system atrophy [ 23 , 24 , 25 ]. ND-13 exerts these protective effects by reducing apoptosis and by inactivating the proapoptotic protein caspase-3 in neuronal cell lines exposed to these neurotoxic insults.…”

Neuroprotective effects of extracellular DJ‐1 on reperfusion injury in SH‐SY5Y cells

“…Recent studies from the Offen laboratory have shown that peptides derived from DJ‐1 is capable of cytoprotection. In these studies, a short DJ‐1‐based peptide named ND‐13 has been shown to protect cell death induced by oxidative stress from 3‐nitropropionic acid, hydrogen peroxide, 6‐OHDA, or DA treatment (Lev et al a; Glat, Ben‐Zur, Barhum, & Offen, ). This ND‐13 peptide also rescued NSC‐34 neuronal cells from peroxynitrite ion generator 3‐morpholinosydnonimine (SIN‐1)‐induced neurotoxicity (Lev, Barhum, Lotan, Steiner, & Offen, b).…”