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• W2991171330 abstract "Article21 November 2019free access Source DataTransparent process LIN28A loss of function is associated with Parkinson's disease pathogenesis Mi-Yoon Chang Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Search for more papers by this author Boram Oh Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jang-Eun Choi Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Yanuar Alan Sulistio Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Hye-Ji Woo Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Ayoung Jo Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Search for more papers by this author Jinil Kim Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Eun-Hee Kim Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Seung Won Kim Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jungwook Hwang Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jungyun Park Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jae-Jin Song Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Oh-Chan Kwon Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Hyongbum Henry Kim Department of Pharmacology, College of Medicine, Yonsei University, Seoul, Korea Search for more papers by this author Young-Hoon Kim Department of Pharmacology, College of Medicine, Yonsei University, Seoul, Korea Search for more papers by this author Joo Yeon Ko Department of Dermatology and Research Institute of Dermatology, University of Hanyang College of Medicine, Hanyang Medical Center, Seoul, Korea Search for more papers by this author Jun Young Heo Department of Biochemistry, Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea Search for more papers by this author Min Joung Lee Department of Biochemistry, Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea Search for more papers by this author Moses Lee Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Search for more papers by this author Murim Choi Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Search for more papers by this author Sun Ju Chung Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Search for more papers by this author Hyun-Seob Lee Corresponding Author [email protected] orcid.org/0000-0001-6230-1405 Genomic Core Facility, Transdisciplinary Research & Collaboration Division, Translational Research Institute, Seoul National University Hospital, Seoul, Korea Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Search for more papers by this author Sang-Hun Lee Corresponding Author [email protected] orcid.org/0000-0001-7553-8188 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Mi-Yoon Chang Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Search for more papers by this author Boram Oh Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jang-Eun Choi Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Yanuar Alan Sulistio Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Hye-Ji Woo Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Ayoung Jo Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Search for more papers by this author Jinil Kim Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Eun-Hee Kim Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Seung Won Kim Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jungwook Hwang Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jungyun Park Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Jae-Jin Song Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Oh-Chan Kwon Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Hyongbum Henry Kim Department of Pharmacology, College of Medicine, Yonsei University, Seoul, Korea Search for more papers by this author Young-Hoon Kim Department of Pharmacology, College of Medicine, Yonsei University, Seoul, Korea Search for more papers by this author Joo Yeon Ko Department of Dermatology and Research Institute of Dermatology, University of Hanyang College of Medicine, Hanyang Medical Center, Seoul, Korea Search for more papers by this author Jun Young Heo Department of Biochemistry, Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea Search for more papers by this author Min Joung Lee Department of Biochemistry, Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea Search for more papers by this author Moses Lee Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Search for more papers by this author Murim Choi Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Search for more papers by this author Sun Ju Chung Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Search for more papers by this author Hyun-Seob Lee Corresponding Author [email protected] orcid.org/0000-0001-6230-1405 Genomic Core Facility, Transdisciplinary Research & Collaboration Division, Translational Research Institute, Seoul National University Hospital, Seoul, Korea Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Search for more papers by this author Sang-Hun Lee Corresponding Author [email protected] orcid.org/0000-0001-7553-8188 Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea Search for more papers by this author Author Information Mi-Yoon Chang1,2,‡, Boram Oh1,2,3,‡, Jang-Eun Choi1,2,3,‡, Yanuar Alan Sulistio1,2,3, Hye-Ji Woo1,2,3, Ayoung Jo1,2, Jinil Kim1,2,3, Eun-Hee Kim1,2,3, Seung Won Kim1,2,3, Jungwook Hwang2,3, Jungyun Park2,3, Jae-Jin Song1,2,3, Oh-Chan Kwon1,2,3, Hyongbum Henry Kim4, Young-Hoon Kim4, Joo Yeon Ko5, Jun Young Heo6, Min Joung Lee6, Moses Lee7, Murim Choi7, Sun Ju Chung8, Hyun-Seob Lee *,9,10 and Sang-Hun Lee *,1,2,3 1Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea 2Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea 3Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea 4Department of Pharmacology, College of Medicine, Yonsei University, Seoul, Korea 5Department of Dermatology and Research Institute of Dermatology, University of Hanyang College of Medicine, Hanyang Medical Center, Seoul, Korea 6Department of Biochemistry, Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea 7Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea 8Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 9Genomic Core Facility, Transdisciplinary Research & Collaboration Division, Translational Research Institute, Seoul National University Hospital, Seoul, Korea 10Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea ‡These authors contributed equally to this work *Corresponding author. Tel: +82 2 2072 4385; E-mail: [email protected] *Corresponding author. Tel: +82 2 2220 0625; Fax: +82 2 2220 2422; E-mail: [email protected] EMBO J (2019)38:e101196https://doi.org/10.15252/embj.2018101196 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients. Synopsis Developmental aspects are recently emphasized as an etiology of Parkinson's disease (PD). Lin28 is a RNA-binding protein identified to have roles in the developing brain. Here, we show PD-associated disease phenotypes are developed in Lin28 conditional knockout mice and in an in vitro human disease model for a loss-of-function variant of LIN28A (arginine to glycine at aa 192, R192G) detected from two young age-onset PD patients. Pathologic findings for Parkinson's disease (PD) are manifested in Lin28 conditional knockout (cKO) mice (Lin28a/b flox/flox, Nestin-Cre). A loss-of-function variant of LIN28A (arginine to glycine at aa 192, R192G) are detected from two young age-onset PD patients. PD-related pathologic phenotypes are present in midbrain-type dopamine (mDA) neurons differentiated from the hESCs and the patient-derived hiPSCs carrying LIN28A (R192G). Behavioral recovery of rats with PD after cell transplantation requires correction of the LIN28A variant in the donor patient (pt)-hiPSCs. Introduction Parkinson's disease (PD) is an insidious movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN) of the midbrain. Although genome-wide association studies (GWAS) and analyses of familial forms of PD have contributed to the identification of genetic backgrounds and risk factors for this disorder, these account for a minority of disease cases (< 5 and < 30% of sporadic and familial PD patients, respectively) (Klein & Westenberger, 2012). To extend our understanding for PD etiologies and thus to develop efficient therapeutic tools, it is also valuable to analyze rare gene mutations that occur in single patients with PD, especially if possible associations between gene dysfunctions and PD pathogenesis have been suggested by pre-existing studies in vitro and/or in vivo using animal models. Recent progress in stem cell research and gene-editing techniques enable analyses using human disease modeling with patient-derived cells and the feasible editing of affected genes. PD is classically regarded as an age-associated disorder. However, juvenile- or early-onset PD cases are not easily explained by age-related processes. Many PD-associated genes (PARK) such as SCNA, PINK1, LRRK2, and VPS35 have been implicated in playing roles in neuronal developmental processes (reviewed in Le Grand et al, 2015). Consistently, a recent study using genome-wide transcriptome analysis has shown RBFOX1, a gene linked to neurodevelopmental diseases, is the most consistently dysregulated gene in PD neurons harboring those PARK gene mutations (Lin et al, 2016). In addition, studies have demonstrated that developmental/perinatal exposure of pesticides or brain insults lead to the dysfunction of the midbrain DA neuron system in adult life, which ultimately causes the development of PD (Thiruchelvam et al, 2002; Richardson et al, 2006; Froudist-Walsh et al, 2017). Thus, similar to Huntington's disease being regarded as a neurodevelopmental disorder (Humbert, 2010; Brennand, 2016), the involvement of developmental defects is suspected as a cause of PD, especially in young age-onset PD cases (Schwamborn, 2018). Lin28a (and its paralog Lin28b in vertebrates) is a highly conserved RNA-binding protein, which is mainly expressed and acts during early embryonic and fetal development (Shyh-Chang & Daley, 2013). Lin28a has been reported to function in neural stem/precursor cell (NSC) self-renewal and neuronal differentiation in the developing brain (Balzer et al, 2010; Patterson et al, 2014; Yang et al, 2015). Forced re-entry of this RNA-binding protein expression in adult tissues enhances tissue repair (Shyh-Chang et al, 2013), a critical molecular event of which is the generation of new tissue-specific cells from stem cells of the tissues. Consistent with the Lin28a roles in stem cells during development and tissue repair, we have recently demonstrated that NSCs cultured from embryonic ventral midbrain (VM) lose their mDA neurogenic potential along with the loss of Lin28a expression (Rhee et al, 2016). In addition, mDA neurons yielded without Lin28a are more vulnerable in toxic environments, all of which are recovered by forced expression of Lin28a in the NSCs, indicating Lin28a functions are required to develop healthy mDA neurons. In this study, to assess whether the loss of Lin28 function during brain development could cause PD, we analyzed the conditional Lin28 deletion in mice. In addition, we detected a loss-of-function variant of LIN28A from two early-onset PD patients and assessed the pathogenic contribution of this variant to the patients’ disease by analyzing isogenic human embryonic stem cells (ESCs) and human induced pluripotent stem cells (hiPSCs) derived from the patients (pt-hiPSCs), in which the variant was inserted or corrected using CRISPR-CAS9-mediated gene editing. Lastly, we show a transplantation study using patient-derived cells in a PD animal model, which suggests a necessity for correction of the variant gene in future personalized cell therapy targeting these patients. Results Reduced mDA neurons along with pathologic axonal sprouting in Nestin-Cre/Lin28 cKO mice Our previous in vitro study (Rhee et al, 2016) suggested that Lin28a expression/function in NSCs cultured from embryonic VM tissues is critical for the generation of healthy mDA neurons. These findings prompted us to assume that a Lin28 deletion/dysfunction in NSCs during development causes a developmental defect in generating mDA neurons resistant against toxic insults and thus ultimately leads to PD-like behaviors with mDA neuronal loss in adult life. To prove the hypothesis, we generated double Lin28a/b conditional knockout (cKO) mice (because Lin28a and Lin28b can compensate for the loss of each other), in which these genes are knocked out in NSCs, by crossing Lin28a/b flox/flox mice with Nestin-Cre heterozygous transgenic mice. Consistent with Lin28 function in NSC self-renewal in developing cortices (Yang et al, 2015), the brain size of Lin28 cKO mice after birth was smaller than their wild-type (WT) littermates by 8% (Appendix Fig S1A). Along with smaller brain size, previous studies have shown that the fractions of cells that had exited the cell cycles (BrdU+/Ki67−) were greater, with a significant reduction of total proliferating cells (BrdU+/Ki67+) and without the change in TUNEL+ cell numbers in the ventricular/subventricular zone of Lin28 KO brains, indicating that reduced brain size in Lin28 KO mice is caused by early cell cycle exit without alteration of cell death (Yang et al, 2015; Herrlinger et al, 2019). In the VM during early development (embryonic day 10.5, E10.5), mRNA expressions of the early developmental genes such as Otx2 (rostral brain patterning) and PLZF (primitive neuroepithelial cell formation) were not altered in Lin28a cKO mice (Appendix Fig S1B). By contrast, expression of the proneural bHLH factors neurogenin 2 (Ngn2) and Mash1, whose expression commences upon neuronal differentiation, was greater in Lin28a/b cKO mice at E10.5–11.5 (Appendix Fig S1B). Afterward, in later embryonic days (E12.5), the proneural factor expression was significantly lower in the cKO VM than in that of their WT littermates (Appendix Fig S1C and D), consistent with the previous finding of premature neuronal differentiation by Lin28a/b deletion. Since NSC differentiation concurs with cell cycle exit, the premature neuronal differentiation and early cell cycle exit observed are likely to be closely linked. Midbrain DA neurons arise from floorplate-like progenitor cells expressing Foxa2 and Lmx1a in the developing midbrain (Ono et al, 2007; Bonilla et al, 2008). We have previously shown that Lin28a positively regulates the mDA-specific developmental gene expressions (Rhee et al, 2016). Consistently, expression of the VM floor plate markers (especially, Lmx1a) was greatly reduced in the Lin28a/b cKO VMs, which was accompanied by a decrease in Nurr1 expression, a transcription factor critical for DA phenotype gene expression (Fig 1A–C). Accordingly, the number of mDA neurons (tyrosine hydroxylase-positive; TH+) generated in the cKO VM was 76% of the WT littermates at embryonic stage (Fig 1D). Collectively, these findings indicate that Lin28 KO during brain development causes premature cell cycle exit and differentiation, defective mDA neurogenesis, and reduced expression of the critical mDA developmental genes. The number of DA neurons in the SN of adult cKO mice was also lower than the WT counterparts, and the reduction was more severe at old ages [(% reduction compared to the WT values: 14% at young age (2–7 months) versus 22% at old age (14–15 months)] (Fig 1E). Figure 1. Developmental defects associated with the pathogenesis of Parkinson's disease (PD) in Nestin-Cre/Lin28a/b conditional knockout (cKO) mice A–C. Defects in midbrain-type dopamine (mDA) neuron-specific developmental factor expressions in the ventral midbrain (VM) of Lin28a/b cKO embryos. Embryonic VM sections from 3 WT and cKO animals each were immunofluorescent stained for the midbrain-specific markers in parallel, and mean fluorescent intensities (MFI) were measured. n = 20 cells for each group. ***P < 0.0001, t-test. D, E. Reduced mDA neurons in the embryonic VM (E12.5) and adult SN at 2–7 months (young age) and at 14–18 months (old age) of the Lin28a/b cKO mice. *P < 0.05, **P < 0.005, ***P < 0.0001, t-test. n = 4 each wild-type (WT) and cKO embryos, and 9 (WT) and 8 (cKO) in adult mice. Scale bars, 100 μm. F, G. Enhanced DA transporter (DAT)+ and TH+ fiber intensities of Lin28a/b cKO adult mice (age: 4–7 months). Striatal sections of WT and cKO mice (3 animals for each group) were subjected to immunofluorescent staining against DAT and TH in parallel, and MFI was measured from 101 microscopic fields of dorsolateral striatum. Scale bars, 200 μm. ***P < 0.0001, t-test. H. DA uptakes assessed by nanoScanPET/MRI analysis using [18F]FP-CIT. Arrows indicate substantia nigra. n = 9 (WT), 8 (cKO). *P < 0.05, ***P < 0.001, t-test. I–M. Enhanced susceptibility of Lin28a/b cKO mice to the parkinsonian toxin MPTP. WT and cKO mice were injected with MPTP (20 mg/kg, i.p) for 5 days, and behaviors of the animals were assessed for 1 month after the MPTP injection (I–K). The mouse brains at 1 month after initial MPTP exposure were subjected to immunohistochemical analyses for TH+ mDA neuron counts at SN (L) and DAT MFI at striatum (M). Dotted line denotes corticostriatal boundary (M). n = 8–13 (WT), 5–9 (cKO). *P < 0.05, **P < 0.01, ***P < 0.0001, t-test. Scale bars, 200 μm. Data information: All data are presented as mean ± SE. Download figure Download PowerPoint This decrease of mDA neuron numbers in Lin28 cKO mice did not cause behavioral deficits associated with PD at least until 15 months of age (Fig 1H–J and data now shown). However, it is of note that the DA transporter (DAT) + and (TH) + fiber intensities in striatum, the target site of mDA neurons in the SN, were significantly greater in the Lin28a/b cKO, compared to their WT littermates (Fig 1F and G), suggesting compensatory “pathologic axonal sprouting” detected in early stages of PD (reviewed in Arkadir et al, 2014). This early PD phenotype in Lin28a/b cKO mice was further confirmed by the increase of striatal DA uptake in a nanoScanPET/MRI analyses (Fig 1H). The pathologic sprouting is associated with increased mDA neuron susceptibility to toxic insults because DA neurotransmitters and DAergic neurotoxins are overloaded in mDA neurons by being transported through increased levels of DAT proteins (axon terminals) per mDA neuron. Consistently, exposure to MPTP, a parkinsonian toxin, led to a more severe loss of mDA neurons in the SN of the Lin28a/b cKO mice (Fig 1L), with reduction in TH and DAT staining at striatum, suggestive of reduced nigro-striatal DA innervation in Lin28/b cKO than WT (Fig 1M). Ultimately, profound behavioral deficits associated with PD were manifested in Lin28a/b cKO mice by the toxin exposure (Fig 1I–K). Taken together, these findings indicate that Lin28 dysfunction during brain development contributes to the genetic risk factor of developing PD by the increased susceptibility of mDA neurons to toxic insult in the adult midbrain. A loss-of-function variant of LIN28A detected in early-onset PD patients An author of this study (HS Lee, male) was diagnosed with typical PD at age 27 in 2003 with reduced DA uptake, especially in the left posterior putamen, in an [18F]-FP-CIT PET scan (Appendix Fig S2A). The patient has been being treated with levodopa since 2006. He developed “on-off symptoms”, exhibiting resting tremor, hypokinetic movements, and rigidity during “off” periods, and only mild parkinsonian symptoms during “on” periods. To control motor complications, he has been receiving liquid levodopa–carbidopa therapy (Yang et al, 2017) since 2013 at Seoul National University Hospital (Seoul, Korea). He has had good L-dopa responsiveness without cognitive decline or other features suggestive of Parkinson-plus. The patient described above has been conducting research as a biologic researcher for the last decade to find out the possible causes of his disease. Whole-exome sequencing (WES) of DNA extracted from his blood identified 145 rare variants after filtering based on variant quality, population frequency, and functional annotation. None of these variants have been detected in genes directly associated with PD pathogenesis (PARK genes). It was very coincident to detect a variant of LIN28A [arginine changed to glycine at amino acid position 192 (aa192); LIN28A(R192G), heterozygous] (Appendix Fig S2B). We detected the same heterozygous LIN28A(R192G) mutation in one more PD patient (male, age: 63, onset age: 49), who was receiving medical treatment at Asan Medical Center, Seoul, Korea. The arginine residue at position 192 (R192) in the LIN28A protein is located in the C-terminal domain, distal to an RNA-binding Zn-knuckle domain (residues 138–176) (Appendix Fig S2B, upper). The sequence alteration from a charged polar amino acid (R) to an uncharged non-polar amino acid (G), with a large difference between hydropathy indices (4.1), might well cause structural changes in the protein (Appendix Fig S2C) that affect LIN28A function. Coincidently, the same R-to-G mutation was detected in the C-terminal region of DNAJC6 (PARK19) among juvenile-onset PD patients (Olgiati et al, 2016). LIN28A(R192G) is identified as a loss-of-function mutation in the analyses of isogenic hESCs carrying the variant As an in vitro human disease model to assess the role of the LIN28A variant (mutation), we established a line of human embryonic stem cells (hESCs) in which the LIN28A sequence was modified to encode the R192G mutation by using a CRISPR-CAS9 nuclease, but they were otherwise isogenic with the parent hESCs. After co-transfecting hESCs (H9) with a single-stranded oligodeoxynucleotide (ssODN) encoding the mutation, a plasmid encoding CAS9," @default.
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• W2991171330 title "<scp>LIN</scp> 28A loss of function is associated with Parkinson's disease pathogenesis" @default.
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