Wednesday, February 5, 2025
2/5/2025
Through our previous work funded by the American Parkinson Disease Association and NINDS, we have discovered a new Parkinson’s disease (PD) genetic locus on the short arm of chromosome 20, and identified a new PD gene, TMEM230. TMEM230 encodes a transmembrane protein of secretory and recycling vesicles, including synaptic vesicles in neurons. TMEM230 is the first transmembrane protein of synaptic vesicles identified in PD to date. Our findings, therefore, directly point to the dysfunction of synaptic vesicles in the pathogenesis of PD. The precise physiological functions of TMEM230, and pathogenic mechanism of the TMEM230-mediated PD remain unclear. Based on the molecular features of TMEM230, and its relationship with synaptic vesicle and endosomal markers tested in our study, we hypothesize that TMEM230 is a trafficking protein of synaptic vesicles, and it may function in synaptic vesicle biogenesis, exocytosis, endocytosis and recycling, and synaptic transmission in neurons. But it remains to be determine where in the subcellular compartments and what functions that TMEM230 plays. In the previous funding cycle, we identified TMEM230 as an endocytic cargo protein that binds to the medium subunit (AP2M1) of adaptor protein 2 complex (AP2) to promote AP2-dependent clathrin-mediated endocytosis; whereas, PD-linked mutations affect this process and impair synaptic vesicle recycling, more specifically, by affecting budding from presynaptic membrane to form new AP2/clathrin-coated recycling vesicles. In this application, we propose three specific aims to determine the physiological function of TMEM230, especially the functional motifs for TMEM230 to bind to AP2M1, and the pathogenic mechanism underlying TMEM230-linked PD. We propose to develop a total of six TMEM230 mouse models in specific aim 1, to perform phenotypical, pathological and biochemical characterization in specific aim 2, and to perform neurophysiological characterization of nigrostriatal pathway in these mouse models in specific aim 3. SV recycling deficits have emerged as a convergent pathogenic pathway underlying PD pathogenesis. There is evidence that LRRK2, auxilin and synaptojanin 1 affect clathrin uncoating; and VPS35 may impair retromer- TGN trafficking. TMEM230 appears to affect a distinct step in SV recycling i.e., budding from the presynaptic membrane to form new AP2/clathrin-coated recycling SVs. A number of important issues remains to be addressed. Based on our resources and expertise, we propose to address some of these issues using relevant mouse models in this application. Successful completion of the proposed studies will provide essential information to understand the physiological function of TMEM230 and the pathogenic mechanism underlying TMEM230-linked PD. Moreover, since TMEM230-linked PD shows clinical and pathological features compatible with those in classical PD, the outcomes from this study may also have important implications in understanding the pathogenic mechanisms in other forms of PD, including sporadic PD.
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