Crosstalk of parkin and Ret in dopaminergic neurons

Recent genetic and functional studies have revealed striking similarities in the protein networks and molecular mechanisms altered in cancer and Parkinson's disease, as illustrated here for the converging signaling pathways of parkin and Ret [1]. These similarities may guide our thinking about potential therapies for both diseases. The proto-oncogene RET encodes a receptor tyrosine kinase that is the canonical glial cell line-derived neurotrophic factor (GDNF) family receptor. The name stands for " rearranged during transfection " since Ret was found to be fused to a putative zinc finger protein rfp in vitro during transfection of human T-cell lymphoma DNA in 3T3 fibroblasts [2]. In the meantime, oncogenic activating mutations in Ret were found to cause multiple endocrine neoplasia type 2 (MEN2), a dominant inherited cancer syndrome that affects neuroendocrine organs such as the thyroid. Conversely, loss-of-function mutations are the main cause of Hirschsprung disease, a congenital absence of enteric ganglia in the hindgut. Interestingly, some mutations can even lead to MEN2 and Hirschsprung disease simultaneously [3]. 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. 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]. Parkin is encoded by the PARK2 gene and was originally identified as a gene mutated in some familial forms of PD. In the meantime, PARK2 mutations have also been found in sporadic forms of PD and account for most autosomal-recessive PD cases [7]. Parkin mutations were also shown to lead to glioblastoma, breast, colon, pancreas, liver and lung cancer [1]. Interestingly, the same mutations could be found in PD and cancer patients, also heterozygosity is sufficient to trigger uncontrolled cancerous cell division, while in PD patients both copies need to be mutated [1]. To investigate a potential crosstalk of parkin and Ret we …