Parkin Protects against Neurotoxicity in the 6-Hydroxydopamine Rat Model for Parkinson's Disease

Abstract

Loss-of-function mutations in the PARK2 gene are the major cause of early onset familial Parkinson's disease. The gene product, parkin, is an E3 ligase of the ubiquitin-proteasome pathway involved in protein degradation. Dopaminergic neuron loss may result from the toxic accumulation of parkin substrates, suggesting a key role for parkin in dopaminergic neuron survival. In this study, we have investigated the neuroprotective capacity of parkin in the 6-OHDA rat model for Parkinson's disease. 6-OHDA induces the generation of reactive oxygen species leading to the degeneration of catecholaminergic neurons, but may also impair proteasome activity. Lentiviral vectors encoding human wild-type parkin or green fluorescent protein were stereotactically injected into the substantia nigra 2 weeks prior to a striatal 6-OHDA lesion. Histological analysis 1 and 3 weeks after lesioning showed a significant preservation of dopaminergic cell bodies and nerve terminals. Moreover, lesioned rats overexpressing parkin displayed a corresponding behavioral improvement as measured by the amphetamine-induced rotation test and the cylinder test. The improved performance in the amphetamine-induced rotation test lasted until 20 weeks after lesioning. Our results demonstrate that parkin acts as a potent neuroprotective agent in vivo against 6-OHDA toxic insults. These data support the therapeutic potential of parkin for the treatment of not only familial but also sporadic Parkinson's disease.

Parkin represses 6-hydroxydopamine-induced apoptosis via stabilizing scaffold protein p62 in PC12 cells

“…Thus, abnormal ERK1/2 activation plays a critical role in PD pathogenesis. Parkin is documented to mediate neuroprotection against 6-OHDA-induced neurotoxicity [7,21,41,42] . As parkin is an E3 ubiquitin ligase, its neuroprotective effect may be executed via its substrates.…”

Programmed Cell Death in Parkinson's Disease

“…Parkin prevents cytochrome c release in an E3 ubiquitin ligase-dependent manner (Darios et al 2003;Berger et al 2009) and protects from apoptosis in dopaminergic neurons (Staropoli et al 2003;Jiang et al 2004), in 6-OHDA-treated rat (Vercammen et al 2006), and in Drosophila by suppressing JNK signaling (Hwang et al 2010). Overexpressing Parkin protects SH-SY5Y cells from 6-OHDA toxicity, whereas genetic ablation of Parkin increases susceptibility of neurons to rotenone (Casarejos et al 2006) and can even cause apoptosis in the absence of a neurotoxin (Machida et al 2005).…”

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

“…Moreover, it has to be mentioned that for immunotherapy, the lentiviral vectors are systemically administered, whereas in the case of gene therapy, the lentiviral vectors are most often administered in the Lentiviral vectors in cancer immunotherapy K Breckpot et al tissue of interest, resulting in transduction of these tissue-specific cells. [157][158][159][160][161] Second, when using ex vivo-transduced DC or targeting DC in vivo, terminally differentiated, nondividing cells are transduced as opposed to extensively proliferating cells in the SCID trial, thereby posing less of a risk for oncogenic transformations. Finally, when an immune response is induced in vivo, the effector cells will most likely kill cells that express the target antigen, including the transduced APC, thus, further reducing the risk for oncogenesis.…”