PMID- 28656059 OWN - NLM STAT- MEDLINE DCOM- 20180305 LR - 20181113 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 7 IP - 7 DP - 2017 TI - Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21. PG - 2033-2045 LID - 10.7150/thno.19824 [doi] AB - 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. FAU - Park, Mi Hee AU - Park MH AD - 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. FAU - Lee, Hwa-Jeong AU - Lee HJ AD - 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. FAU - Lee, Hye Lim AU - Lee HL AD - 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. FAU - Son, Dong Ju AU - Son DJ AD - 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. FAU - Ju, Jung Hoon AU - Ju JH AD - 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. FAU - Hyun, Byung Kook AU - Hyun BK AD - 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. FAU - Jung, Sung Hee AU - Jung SH AD - 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. FAU - Song, Ju-Kyoung AU - Song JK AD - 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. FAU - Lee, Dong Hun AU - Lee DH AD - 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. FAU - Hwang, Chul Ju AU - Hwang CJ AD - 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. FAU - Han, Sang Bae AU - Han SB AD - 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. FAU - Kim, Sanghyeon AU - Kim S AD - Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD 20850. FAU - Hong, Jin Tae AU - Hong JT AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170512 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (CDKN1A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p21) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.3.2.27 (parkin protein) RN - EC 2.7.12.2 (MAP Kinase Kinase 4) SB - IM MH - Animals MH - *Cell Differentiation MH - Cyclin-Dependent Kinase Inhibitor p21/*metabolism MH - Humans MH - MAP Kinase Kinase 4/*metabolism MH - Mice MH - Mice, Knockout MH - Neural Stem Cells/*physiology MH - *Proteolysis MH - Ubiquitin-Protein Ligases/genetics/*metabolism PMC - PMC5485421 OTO - NOTNLM OT - PARK2 OT - p21 COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2017/06/29 06:00 MHDA- 2018/03/06 06:00 PMCR- 2017/01/01 CRDT- 2017/06/29 06:00 PHST- 2017/02/26 00:00 [received] PHST- 2017/03/31 00:00 [accepted] PHST- 2017/06/29 06:00 [entrez] PHST- 2017/06/29 06:00 [pubmed] PHST- 2018/03/06 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - thnov07p2033 [pii] AID - 10.7150/thno.19824 [doi] PST - epublish SO - Theranostics. 2017 May 12;7(7):2033-2045. doi: 10.7150/thno.19824. eCollection 2017.