Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism

Abstract

The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.

6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway

“…To evaluate whether PARK7 secretion was mediated by the conventional ER-/Golgi-dependent secretion mechanism, cells were treated with brefeldin A, an inhibitor of ER-Golgi transport, as a result of which it was found that treatment with brefeldin A inhibited FN1 secretion but not PARK7 secretion (Figure 1(C), suggesting that the conventional secretory pathway was not involved in PARK7 secretion. As previously reported [9,10], most of PARK7 was found to be in the cytosolic protein-enriched fraction obtained by subcellular fractionation (Figure 1(D)), supporting the idea that PARK7 was secreted via an ER-/Golgi-independent secretory pathway. We also used 2D-PAGE to examine the oxidative state of PARK7, as a result of which we found that the ratio of oxPARK7 to total PARK7 in medium was almost the same as that in cells, suggesting that secretion of PARK7 was not induced by its oxidation (Figure 1(E)).

10.1080/15548627.2018.1493043-F0001Figure 1.PARK7 was secreted from SH-SY5Y cells.

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“…PARK7 has been implicated as a protein encoded by one of the causative genes ( PARK7 ) in a familial form of Parkinson disease (PD) [10]. It has also been suggested that PARK7 is related to a sporadic form of PD [11,12].…”

“…PARK7 is localized in the cytoplasm and the nucleus; it has also been shown that some PARK7 is localized in the mitochondria [9,10,19,20]. Several lines of evidence suggest that PARK7 is secreted from cells into the circulation despite the fact that PARK7 lacks a secretory signal sequence [21–29].…”

Polygenic risk of Parkinson disease is correlated with disease age at onset

“…The identification of rare highly penetrant mutations in genes causing familial and early onset Parkinson disease (PD)1, 2, 3, 4, 5 has considerably improved our understanding of disease pathogenesis. Recently, our understanding of idiopathic PD has been enhanced by genome‐wide association (GWA) studies6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 that have collectively identified PD risk variants at >18 loci 6, 7.…”

Gene therapy progress and prospects: Parkinson's disease

“…Intriguingly, a-synuclein is a substrate of Parkin, 28 linking the two dissimilar proteins into a common functional pathway. Pathogenic mutations resulting in a PD phenotype have recently been described in two other genes: DJ-1, of unknown function, 29 and NR4A2, encoding Nurr-1, a nuclear receptor (see above). 30 Elucidation of the pathways involved in genetic forms of PD has provided new animal models of specific SN degeneration, which do not rely on toxicity caused by chemical insults.…”