Abstract
Mutations in transmembrane protein 230 (TMEM230) gene are suggested to be associated with the autosomal dominant Parkinson’s disease (PD) with typical movement disorders and Lewy body pathology. However, the normal functions and the pathological roles of TMEM230 are not clear. In this study, we used TMEM230 isoform II constructs including wild-type (WT) and four reported PD-linked mutation constructs (Y92C, R141L, 184Wext*5, and 184PGext*5). Ectopic expression of WT and PD-linked mutant TMEM230 variants in cultured cells dramatically induced apoptotic cell death compared with that of vector control cells. Mutant TMEM230 caused cell toxicity at an increased severity than WT TMEM230. Moreover, expression of TMEM230 increased mitochondrial reactive oxygen species (ROS) levels, decreased cellular ATP, activated caspase 3/7, and increased poly(ADP-ribose) polymerase-1 (PARP1) cleavage. Treatment with N-acetylcysteine (NAC; an ROS scavenger) or Z-VAD-FMK (a caspase inhibitor) significantly attenuated TMEM230-induced apoptosis in both cultured cells and primary neurons. Our results indicated that TMEM230 mediated a PARP1-linked apoptotic cell death pathway. These findings not only provide the novel insight into the biological roles of TMEM230 in the PARP1-linked pathway but also provide a TMEM230-induced cell death mechanism underlying PD pathogenesis.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disease with movement disorder
To further study transmembrane protein 230 (TMEM230)-induced cell death, we used Hoechst 33342 nuclei staining to identify high condensation and fragmented nuclei. Both WT and mutant TMEM230 caused apoptosis, whereas PD-linked mutant caused more apoptotic cell death (Figures 1D,E). These results suggest that TMEM230 is critical for controlling apoptotic cell death
The major findings of this study were that ectopic expression of both WT and PD-linked mutant TMEM230 induced apoptotic cell death through mitochondrial dysfunction, caspase activation, and poly(ADP-ribose) polymerase-1 (PARP1) cleavage
Summary
Parkinson’s disease (PD) is a common neurodegenerative disease with movement disorder. The clinical features of PD include tremors, muscle rigidity, bradykinesia, and postural instability in movements due to selective loss of dopaminergic neurons in the brain (Shi et al, 2017). PD affects about 1% of individuals aged over 60 years and about 4–5% of those aged over 85 years (Lew, 2007). The molecular pathogenesis is not completely understood (Yarnall et al, 2012). Mutations in several genes have been identified to be associated with familial form of PD, including α-synuclein, LRRK2, parkin, PINK1, DJ-1, VPS35, and recently identified transmembrane protein 230 (TMEM230; Williams-Gray and Worth, 2016)
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