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

Extracellular Alpha-Synuclein Oligomers Induce Parkin S-Nitrosylation: Relevance to Sporadic Parkinson’s Disease Etiopathology

“…***p < 0.001 compared to control; &&& p < 0.001 compared to parkin overexpressed cells; ##p < 0.01 compared to control + ASN, using two-way ANOVA followed by Bonferroni post hoc test against ASN oligomer toxicity. These findings are in agreement with currently emerging evidence indicating parkin as an important neuroprotective protein [60][61][62]. Previous reports demonstrated that E3 ubiquitin ligase activity of parkin was involved in many mechanisms regulating cell viability, such as, for example, governing mitochondrial quality control by triggering selective mitophagy [63] or participation in protein degradation during ER stress [64].…”

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“…Ret/GDNF signaling has also been shown to have many important functions in the mammalian body, including affecting the survival of midbrain dopaminergic neurons of the substantia nigra, which preferentially die in Parkinson's disease (PD) patients [2]. Thus far, we could show in three different Ret-deficient mouse lines that specifically substantia nigra dopaminergic neurons die progressively with age, suggesting a cell-autonomous maintenance function of Ret in these neurons [4,5]. To date no Ret mutations were found in PD patients, most likely because Ret mutations are frequently life-threatening.…”

“…To date no Ret mutations were found in PD patients, most likely because Ret mutations are frequently life-threatening. But recently we could show that Ret is tightly linked to the protein network altered in PD patients and crosstalks directly with proteins like the redox-dependent molecular chaperone and oncogene DJ-1 and the E3 ubiquitin protein ligase and tumor suppressor protein parkin [5,6].…”

“…To address the molecular mechanisms of this genetic crosstalk between parkin and Ret, we went ahead and focused on analyzing the effect on mitochondria in more detail [5]. We found that down-regulation of both parkin and Ret led to impaired mitochondrial function and morphology and that parkin and GDNF/Ret can substitute for each other to ensure proper mitochondrial function by converging signaling cascades activating the nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB).…”

Progress and potential impact of RET kinase targeting in cancer

“…RET has important embryonic roles in the development, maturation, and survival of neurons in the central and peripheral nervous systems, but its roles in adult neural cell types are more varied and less well defined. Current data suggest that RET activity is not essential for survival of these cells under normal conditions but that RET may be required for survival of aging or damaged nerves [17][18][19]. Thus, ablation of RET over prolonged periods may sensitize mature neurons to other types of damage or neuronal degeneration.…”