Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons

Abstract

A mouse genetic study reveals a novel cell-survival role for the Parkinson's disease-associated gene DJ-1 in dopaminergic neurons that have reduced support from endogenous survival factors.

Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration

“…Both parkin signaling and GDNF/RET signaling are required behaviors, such as movement, memory, motivation, and emotions (22,42). Consistent with this rationale, we could detect changes in motor and emotional behavior in RET KO and RET/parkin DKO mice (Figure 3), which we did not observe in previously reported RET and RET/DJ-1 KO mice (4,6). The lack of GDNF to stimulate mitochondrial biogenesis is in contrast to other trophic and neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor, and EGF, for which this has been reported (43).…”

“…Interestingly, in the RET-deficient background, DJ-1 seems to be essential only for DA cell body survival (6). Here, we found that parkin is important for cell body and axonal maintenance and has also a minor effect on dopamine levels in the striatum (Figures 1 and 2).…”

“…Why the DA system depends on neurotrophic GDNF/RET signaling and which downstream signaling cascades are used for their beneficial effect is still unknown. In addition, we found that RET and DJ-1, a protein mutated in rare familial forms of PD, are required to ensure DA cell body maintenance through the RAS/MAPK pathway (6).…”

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

“…Deletion and point mutations of DJ-1 have been shown to be responsible for onset of familial Parkinson's disease, PARK7 [5]. DJ-1 is a multi-functional protein and plays roles in transcriptional regulation [8][9][10][11][12][13][14][15] and in modulation of signaling cascades [16][17][18][19][20] through protein-protein interaction, leading to anti-oxidative stress function [21][22][23]. Furthermore, we have reported that DJ-1 activated TH and DDC through direct binding to TH and DDC in an oxidative status of DJ-1-dependent manner [24] and that human DJ-1 activates TH gene expression in cultured human dopaminergic cells [15].…”

Changes in the two‐dimensional electrophoresis pattern of the Parkinson's disease related protein DJ‐1 in human SH‐SY5Y neuroblastoma cells after dopamine treatment

“…Increase in DJ-1 expression may be induced by ROS and DJ-1 overexpression specifically protects against dopamine toxicity (23,24); more specifically, a compensatory upregulation of DJ-1 and parkin has been reported in the brain of a A53T a-synuclein mouse model treated with the mitochondrial toxin rotenone (25); eventually, DJ-1 is indispensable for the survival of dopaminergic neurons lacking the GDNF-receptor Ret (26). DJ-1 appears thus to display a multifaceted function that is further regulated by the interaction with cytosolic and mitochondrial proteins (27).…”