Theranostics 2017; 7(7):2033-2045. doi:10.7150/thno.19824 This issue Cite

Research Paper

Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21

Mi Hee Park1, Hwa-Jeong Lee1, Hye Lim Lee1, Dong Ju Son1, Jung Hoon Ju1, Byung Kook Hyun1, Sung Hee Jung1, Ju-Kyoung Song1, Dong Hun Lee1, Chul Ju Hwang1, Sang Bae Han1, Sanghyeon Kim2✉, Jin Tae Hong1✉

1. College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongwon-gun, Chungbuk, Republic of Korea, 361-951;
2. Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD 20850.

Citation:
Park MH, Lee HJ, Lee HL, Son DJ, Ju JH, Hyun BK, Jung SH, Song JK, Lee DH, Hwang CJ, Han SB, Kim S, Hong JT. Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21. Theranostics 2017; 7(7):2033-2045. doi:10.7150/thno.19824. https://www.thno.org/v07p2033.htm
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Abstract

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PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in the development of Parkinson's disease (PD). Although the neuroprotective role of parkin is well known, the mechanism of PARK2's function in neural stem differentiation has not yet been thoroughly studied. Co-expressions network analysis showed that synaptosomal-associated protein 25 (SNAP-25) and brain-derived neurotrophic factor (BDNF) were positively correlated with parkin, but negatively correlated with p21 in human patient brain. We investigated a link between the ubiquitin E3 ligase parkin and proteasomal degradation of p21 for the control of neural stem cell differentiation. We found that the neurogenesis was lowered in PARK2 knockout (KO) mice compared with non-tg mice. Expression of the marker protein for neural cell differentiation such as class III beta tubulin (TUBBIII), glial fibrillary acidic protein (GFAP) and neurofilament, as well as SNAP25 and BDNF, was down regulated in PARK2 KO mice. Associated with the loss of differentiation function, p21 protein was highly accumulated in the neural stem cells of PARK2 KO mice. We discovered that p21 directly binds with parkin and is ubiquitinated by parkin which resulted in the loss of cell differentiation ability. Introduction of p21 shRNA in PARK2 KO mice significantly rescued the differentiation efficacy as well as SNAP25 and BDNF expression. c-Jun N-terminal kinase (JNK) pathway is implicated in neurogenesis and p21 degradation. We also defined the decreased p21 ubiquitination and differentiation ability were reversed after treatment with JNK inhibitor, SP600125 in PARK2 KO mice derived neural stem cells. Thus, the present study indicated that parkin knockout inhibits neural stem cell differentiation by JNK-dependent proteasomal degradation of p21.

Keywords: PARK2, p21


Citation styles

APA
Park, M.H., Lee, H.J., Lee, H.L., Son, D.J., Ju, J.H., Hyun, B.K., Jung, S.H., Song, J.K., Lee, D.H., Hwang, C.J., Han, S.B., Kim, S., Hong, J.T. (2017). Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21. Theranostics, 7(7), 2033-2045. https://doi.org/10.7150/thno.19824.

ACS
Park, M.H.; Lee, H.J.; Lee, H.L.; Son, D.J.; Ju, J.H.; Hyun, B.K.; Jung, S.H.; Song, J.K.; Lee, D.H.; Hwang, C.J.; Han, S.B.; Kim, S.; Hong, J.T. Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21. Theranostics 2017, 7 (7), 2033-2045. DOI: 10.7150/thno.19824.

NLM
Park MH, Lee HJ, Lee HL, Son DJ, Ju JH, Hyun BK, Jung SH, Song JK, Lee DH, Hwang CJ, Han SB, Kim S, Hong JT. Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21. Theranostics 2017; 7(7):2033-2045. doi:10.7150/thno.19824. https://www.thno.org/v07p2033.htm

CSE
Park MH, Lee HJ, Lee HL, Son DJ, Ju JH, Hyun BK, Jung SH, Song JK, Lee DH, Hwang CJ, Han SB, Kim S, Hong JT. 2017. Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21. Theranostics. 7(7):2033-2045.

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