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1. Parkin coregulates glutathione metabolism in adult mammalian brain

Author

El Kodsi, Daniel N., Tokarew, Jacqueline M., Sengupta, Rajib, Lengacher, Nathalie A., Chatterji, Ajanta, Nguyen, Angela P., Boston, Heather, Jiang, Qiubo, Palmberg, Carina, Pileggi, Chantal, Holterman, Chet E., Shutinoski, Bojan, Li, Juan, Fehr, Travis K., LaVoie, Matthew J., Ratan, Rajiv R., Shaw, Gary S., Takanashi, Masashi, Hattori, Nobutaka, Kennedy, Christopher R., Harper, Mary-Ellen, Holmgren, Arne, Tomlinson, Julianna J., and Schlossmacher, Michael G.

Published
2023
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6. Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites

Author

Tokarew, Jacqueline M., El-Kodsi, Daniel N., Lengacher, Nathalie A., Fehr, Travis K., Nguyen, Angela P., Shutinoski, Bojan, O’Nuallain, Brian, Jin, Ming, Khan, Jasmine M., Ng, Andy C. H., Li, Juan, Jiang, Qiubo, Zhang, Mei, Wang, Liqun, Sengupta, Rajib, Barber, Kathryn R., Tran, An, Im, Doo Soon, Callaghan, Steve, Park, David S., Zandee, Stephanie, Dong, Xiajun, Scherzer, Clemens R., Prat, Alexandre, Tsai, Eve C., Takanashi, Masashi, Hattori, Nobutaka, Chan, Jennifer A., Zecca, Luigi, West, Andrew B., Holmgren, Arne, Puente, Lawrence, Shaw, Gary S., Toth, Gergely, Woulfe, John M., Taylor, Peggy, Tomlinson, Julianna J., and Schlossmacher, Michael G.

Published
2021
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8. Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan

Author

Li, Yuanzhe, Ikeda, Aya, Yoshino, Hiroyo, Oyama, Genko, Kitani, Mitsuhiro, Daida, Kensuke, Hayashida, Arisa, Ogaki, Kotaro, Yoshida, Kousuke, Kimura, Takashi, Nakayama, Yoshiaki, Ito, Hidefumi, Sugeno, Naoto, Aoki, Masashi, Miyajima, Hiroaki, Kimura, Katsuo, Ueda, Naohisa, Watanabe, Masao, Urabe, Takao, Takanashi, Masashi, Funayama, Manabu, Nishioka, Kenya, and Hattori, Nobutaka

Published
2020
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13. Association between Genetic Variation in the TAS2R38 Bitter Taste Receptor and Propylthiouracil Bitter Taste Thresholds among Adults Living in Japan Using the Modified 2AFC Procedure with the Quest Method

Author

Aoki, Kyoko, primary, Mori, Kanetaka, additional, Iijima, Shohei, additional, Sakon, Masato, additional, Matsuura, Nariaki, additional, Kobayashi, Tsuneto, additional, Takanashi, Masashi, additional, Yoshimura, Takeshi, additional, Mori, Norio, additional, and Katayama, Taiichi, additional

Published
2023
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14. The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1

Author

Hayashida, Arisa, Li, Yuanzhe, Yoshino, Hiroyo, Daida, Kensuke, Ikeda, Aya, Ogaki, Kotaro, Fuse, Atsuhito, Mori, Akio, Takanashi, Masashi, Nakahara, Toshiki, Yoritaka, Asako, Tomizawa, Yuji, Furukawa, Yoshiaki, Kanai, Kazuaki, Nakayama, Yoshiaki, Ito, Hidefumi, Ogino, Mieko, Hattori, Yuko, Hattori, Tatsuya, Ichinose, Yuta, Takiyama, Yoshihisa, Saito, Tsukasa, Kimura, Takashi, Aizawa, Hitoshi, Shoji, Hiroshi, Mizuno, Yuri, Matsushita, Takuya, Sato, Mitsuto, Sekijima, Yoshiki, Morita, Masayo, Iwasaki, Akio, Kusaka, Hirofumi, Tada, Mikiko, Tanaka, Fumiaki, Sakiyama, Yusuke, Fujimoto, Takeshi, Nagara, Yuko, Kashihara, Kenichi, Todo, Hiroyuki, Nakao, Kouichi, Tsuruta, Kazuhito, Yoshikawa, Masaaki, Hara, Hideo, Yokote, Hiroaki, Murase, Nagako, Nakamagoe, Kiyotaka, Tamaoka, Akira, Takamiya, Motonori, Morimoto, Nobutoshi, Nokura, Kazuya, Kako, Tetsuharu, Funayama, Manabu, Nishioka, Kenya, and Hattori, Nobutaka

Published
2021
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15. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR (ProtectMove, MiRisk) [sponsor], DFG (ProtectMove) [sponsor], BMBF (MitoPD) [sponsor], Trinh, Joanne, Hicks, Andrew A., König, Inke R., Delcambre, Sylvie, Lüth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilariño-Güell, Carles, Hentati, Faycel, Germer, Elisabeth L., Bauer, Peter, Takanashi, Masashi, Kostić, Vladimir, Lang, Anthony E., Brüggemann, Norbert, Pramstaller, Peter P., Pichler, Irene, Rajput, Alex, Hattori, Nobutaka, Farrer, Matthew J., Lohmann, Katja, Weissensteiner, Hansi, May, Patrick, Klein, Christine, Grünewald, Anne, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR (ProtectMove, MiRisk) [sponsor], DFG (ProtectMove) [sponsor], BMBF (MitoPD) [sponsor], Trinh, Joanne, Hicks, Andrew A., König, Inke R., Delcambre, Sylvie, Lüth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilariño-Güell, Carles, Hentati, Faycel, Germer, Elisabeth L., Bauer, Peter, Takanashi, Masashi, Kostić, Vladimir, Lang, Anthony E., Brüggemann, Norbert, Pramstaller, Peter P., Pichler, Irene, Rajput, Alex, Hattori, Nobutaka, Farrer, Matthew J., Lohmann, Katja, Weissensteiner, Hansi, May, Patrick, Klein, Christine, and Grünewald, Anne

Abstract

Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.

Published
2023

18. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease

Author

Trinh, Joanne, primary, Hicks, Andrew A, additional, König, Inke R, additional, Delcambre, Sylvie, additional, Lüth, Theresa, additional, Schaake, Susen, additional, Wasner, Kobi, additional, Ghelfi, Jenny, additional, Borsche, Max, additional, Vilariño-Güell, Carles, additional, Hentati, Faycel, additional, Germer, Elisabeth L, additional, Bauer, Peter, additional, Takanashi, Masashi, additional, Kostić, Vladimir, additional, Lang, Anthony E, additional, Brüggemann, Norbert, additional, Pramstaller, Peter P, additional, Pichler, Irene, additional, Rajput, Alex, additional, Hattori, Nobutaka, additional, Farrer, Matthew J, additional, Lohmann, Katja, additional, Weissensteiner, Hansi, additional, May, Patrick, additional, Klein, Christine, additional, and Grünewald, Anne, additional

Published
2022
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19. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.

Author

Trinh, Joanne, Hicks, Andrew A, König, Inke R, Delcambre, Sylvie, Lüth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilariño-Güell, Carles, Hentati, Faycel, Germer, Elisabeth L, Bauer, Peter, Takanashi, Masashi, Kostić, Vladimir, Lang, Anthony E, Brüggemann, Norbert, Pramstaller, Peter P, Pichler, Irene, and Rajput, Alex

Subjects
MITOCHONDRIAL DNA, PARKINSON'S disease, GENE expression, MELAS syndrome, LEBER'S hereditary optic atrophy
Abstract

Biallelic mutations in PINK1 / PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1 / PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1 / PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74–0.93). Biallelic PINK1 / PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1 / PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1 / PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS

Author

Ogaki, Kotaro, Li, Yuanzhe, Takanashi, Masashi, Ishikawa, Kei-Ichi, Kobayashi, Tomonori, Nonaka, Takashi, Hasegawa, Masato, Kishi, Masahiko, Yoshino, Hiroyo, Funayama, Manabu, Tsukamoto, Tetsuro, Shioya, Keiichi, Yokochi, Masayuki, Imai, Hisamasa, Sasaki, Ryogen, Kokubo, Yasumasa, Kuzuhara, Shigeki, Motoi, Yumiko, Tomiyama, Hiroyuki, and Hattori, Nobutaka

Published
2013
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26. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1- and PRKN-linked Parkinson's disease 2022.05.17.22275087

Author

Trinh, Joanne, Hicks, Andrew A., Koenig, Inke R., Delcambre, Sylvie, Lueth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilarino-Guell, Carles, Hentati, Faycel, Germer, Elisabeth L., Bauer, Peter, Takanashi, Masashi, Kostic, Vladimir, Lang, Anthony E., Brueggeman, Norbert, Pramstaller, Peter P., Pichler, Irene, Rajput, Alex, Hattori, Nobutaka, Farrer, Matthew J., Lohmann, Katja, May, Patrick, Weissensteiner, Hansi, Klein, Christine, Grünewald, Anne, FNR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (A. Grünewald Group) [research center]

Subjects
Neurologie [D14] [Sciences de la santé humaine], Parkinson's disease, PINK1, Neurology [D14] [Human health sciences], MtDNA, heteroplasmy, PRKN, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract

Biallelic mutations in PINK1 and PRKN cause recessively inherited Parkinson's disease (PD). Though some studies suggest that PINK1/PRKN monoallelic mutations may not contribute to risk, deep phenotyping assessment showed that PINK1 or PRKN monoallelic pathogenic variants were at a significantly higher rate in PD compared to controls. Given the established role of PINK1 and Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as potential disease modifiers in carriers of mutations in these genes. MtDNA integrity, global gene expression and serum cytokine levels were investigated in a large collection of biallelic (n=84) and monoallelic (n=170) carriers of PINK1/PRKN mutations, iPD patients (n=67) and controls (n=90). Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC=0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p=0.0006, Z=3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived and postmortem midbrain neurons from biallelic PRKN-PD patients. Lastly, the heteroplasmic mtDNA variant load was found to correlate with IL6 levels in PINK1/PRKN mutation carriers (r=0.57, p=0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner. MtDNA variant load over time is a potential marker of disease manifestation in PINK1/PRKN mutation carriers.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe authors wish to thank the many patients and their families who volunteered, and the efforts of the many clinical teams involved. Funding has been obtained from the German Research Foundation (ProtectMove; FOR 2488, GR 3731/5-1; SE 2608/2-1; KO 2250/7-1), the Luxembourg National Research Fund in the ATTRACT (Model-IPD, FNR9631103), NCER-PD (FNR11264123) and INTER programmes (ProtectMove, FNR11250962; MiRisk-PD, C17/BM/11676395, NB 4328/2-1), the BMBF (MitoPD), the Hermann and Lilly Schilling Foundation, the European Community (SysMedPD), the Canadian Institutes of Health Research (CIHR), Peter and Traudl Engelhorn Foundation. Initial studies in Tunisia on familial parkinsonism were in collaboration with Lefkos Middleton, Rachel Gibson, and the GlaxoSmithKline PD Programme Team (2002-2005). We would like to thank Dr Helen Tuppen from the Welcome Trust Centre for Mitochondrial Research, Newcastle University, UK for providing us with the plasmid p7D1. Moreover, this project was supported by the high throughput/high content screening platform and HPC facility at the Luxembourg Centre for Systems Biomedicine, and the University of Luxembourg.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:University of Lubeck Ethics CommitteeI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

Published
2022

27. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1- and PRKN-linked Parkinson's disease 2022.05.17.22275087

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (A. Grünewald Group) [research center], FNR [sponsor], Trinh, Joanne, Hicks, Andrew A., Koenig, Inke R., Delcambre, Sylvie, Lueth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilarino-Guell, Carles, Hentati, Faycel, Germer, Elisabeth L., Bauer, Peter, Takanashi, Masashi, Kostic, Vladimir, Lang, Anthony E., Brueggeman, Norbert, Pramstaller, Peter P., Pichler, Irene, Rajput, Alex, Hattori, Nobutaka, Farrer, Matthew J., Lohmann, Katja, May, Patrick, Weissensteiner, Hansi, Klein, Christine, Grünewald, Anne, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (A. Grünewald Group) [research center], FNR [sponsor], Trinh, Joanne, Hicks, Andrew A., Koenig, Inke R., Delcambre, Sylvie, Lueth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilarino-Guell, Carles, Hentati, Faycel, Germer, Elisabeth L., Bauer, Peter, Takanashi, Masashi, Kostic, Vladimir, Lang, Anthony E., Brueggeman, Norbert, Pramstaller, Peter P., Pichler, Irene, Rajput, Alex, Hattori, Nobutaka, Farrer, Matthew J., Lohmann, Katja, May, Patrick, Weissensteiner, Hansi, Klein, Christine, and Grünewald, Anne

Abstract

Biallelic mutations in PINK1 and PRKN cause recessively inherited Parkinson's disease (PD). Though some studies suggest that PINK1/PRKN monoallelic mutations may not contribute to risk, deep phenotyping assessment showed that PINK1 or PRKN monoallelic pathogenic variants were at a significantly higher rate in PD compared to controls. Given the established role of PINK1 and Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as potential disease modifiers in carriers of mutations in these genes. MtDNA integrity, global gene expression and serum cytokine levels were investigated in a large collection of biallelic (n=84) and monoallelic (n=170) carriers of PINK1/PRKN mutations, iPD patients (n=67) and controls (n=90). Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC=0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p=0.0006, Z=3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived and postmortem midbrain neurons from biallelic PRKN-PD patients. Lastly, the heteroplasmic mtDNA variant load was found to correlate with IL6 levels in PINK1/PRKN mutation carriers (r=0.57, p=0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner. MtDNA variant load over time is a potential marker of disease manifestation in PINK1/PRKN mutation carriers.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe authors wish to thank the many patients and their families who volunteered, and the efforts of the many clinical teams involved. Funding has been obtained from the German Research Foundation (ProtectMove; FOR 2488, GR 3731/5-1; SE 2608/2-1; KO 2250/7-1), the Luxembourg National Research Fund in the ATTRACT (Model-IPD, FNR9631103), NCER-PD (FNR112641

Published
2022

28. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR (ProtectMove, MiRisk) [sponsor], DFG (ProtectMove) [sponsor], BMBF (MitoPD) [sponsor], Trinh, Joanne, Hicks, Andrew A., König, Inke R., Delcambre, Sylvie, Lüth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilariño-Güell, Carles, Hentati, Faycel, Germer, Elisabeth L., Bauer, Peter, Takanashi, Masashi, Kostić, Vladimir, Lang, Anthony E., Brüggemann, Norbert, Pramstaller, Peter P., Pichler, Irene, Rajput, Alex, Hattori, Nobutaka, Farrer, Matthew J., Lohmann, Katja, Weissensteiner, Hansi, May, Patrick, Klein, Christine, Grünewald, Anne, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB) [research center], Fonds National de la Recherche - FnR (ProtectMove, MiRisk) [sponsor], DFG (ProtectMove) [sponsor], BMBF (MitoPD) [sponsor], Trinh, Joanne, Hicks, Andrew A., König, Inke R., Delcambre, Sylvie, Lüth, Theresa, Schaake, Susen, Wasner, Kobi, Ghelfi, Jenny, Borsche, Max, Vilariño-Güell, Carles, Hentati, Faycel, Germer, Elisabeth L., Bauer, Peter, Takanashi, Masashi, Kostić, Vladimir, Lang, Anthony E., Brüggemann, Norbert, Pramstaller, Peter P., Pichler, Irene, Rajput, Alex, Hattori, Nobutaka, Farrer, Matthew J., Lohmann, Katja, Weissensteiner, Hansi, May, Patrick, Klein, Christine, and Grünewald, Anne

Abstract

Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.

Published
2022

29. Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation.

Author

Wasner, Kobi, Smajic, Semra, Ghelfi, Jenny, Delcambre, Sylvie, Prada-Medina, Cesar A., Knappe, Evelyn, Arena, Giuseppe, Mulica, Patrycja, Agyeah, Gideon, Rakovic, Aleksandar, Boussaad, Ibrahim, Badanjak, Katja, Ohnmacht, Jochen, Gerardy, Jean-Jacques, Takanashi, Masashi, Trinh, Joanne, Mittelbronn, Michel, Hattori, Nobutaka, Klein, Christine, Antony, Paul, Seibler, Philip, Spielmann, Malte, Pereira, Sandro L., Grünewald, Anne, Wasner, Kobi, Smajic, Semra, Ghelfi, Jenny, Delcambre, Sylvie, Prada-Medina, Cesar A., Knappe, Evelyn, Arena, Giuseppe, Mulica, Patrycja, Agyeah, Gideon, Rakovic, Aleksandar, Boussaad, Ibrahim, Badanjak, Katja, Ohnmacht, Jochen, Gerardy, Jean-Jacques, Takanashi, Masashi, Trinh, Joanne, Mittelbronn, Michel, Hattori, Nobutaka, Klein, Christine, Antony, Paul, Seibler, Philip, Spielmann, Malte, Pereira, Sandro L., and Grünewald, Anne

Abstract

BACKGROUND: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons. OBJECTIVES: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level. METHODS: We generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron-microglia co-cultures. RESULTS: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron-microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS. CONCLUSIONS: Our findings suggest that parkin coregu

Published
2022

30. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1- and PRKN-linked Parkinson’s disease

Author

Trinh, Joanne, primary, Hicks, Andrew A., additional, König, Inke R., additional, Delcambre, Sylvie, additional, Lüth, Theresa, additional, Schaake, Susen, additional, Wasner, Kobi, additional, Ghelfi, Jenny, additional, Borsche, Max, additional, Vilariño-Güell, Carles, additional, Hentati, Faycel, additional, Germer, Elisabeth L., additional, Bauer, Peter, additional, Takanashi, Masashi, additional, Kostić, Vladimir, additional, Lang, Anthony E., additional, Brüggemann, Norbert, additional, Pramstaller, Peter P., additional, Pichler, Irene, additional, Rajput, Alex, additional, Hattori, Nobutaka, additional, Farrer, Matthew J., additional, Lohmann, Katja, additional, Weissensteiner, Hansi, additional, May, Patrick, additional, Klein, Christine, additional, and Grünewald, Anne, additional

Published
2022
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31. Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation

Author

Wasner, Kobi, primary, Smajic, Semra, additional, Ghelfi, Jenny, additional, Delcambre, Sylvie, additional, Prada‐Medina, Cesar A., additional, Knappe, Evelyn, additional, Arena, Giuseppe, additional, Mulica, Patrycja, additional, Agyeah, Gideon, additional, Rakovic, Aleksandar, additional, Boussaad, Ibrahim, additional, Badanjak, Katja, additional, Ohnmacht, Jochen, additional, Gérardy, Jean‐Jacques, additional, Takanashi, Masashi, additional, Trinh, Joanne, additional, Mittelbronn, Michel, additional, Hattori, Nobutaka, additional, Klein, Christine, additional, Antony, Paul, additional, Seibler, Philip, additional, Spielmann, Malte, additional, Pereira, Sandro L., additional, and Grünewald, Anne, additional

Published
2022
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34. Clinical Heterogeneity of Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Caused by MAPT N279K Mutation in Relation to Tau Positron Emission Tomography Features

Author

Ikeda, Aya, Shimada, Hitoshi, Nishioka, Kenya, Takanashi, Masashi, Hayashida, Arisa, Li, Yuanzhe, Yoshino, Hiroyo, Funayama, Manabu, Ueno, Yuji, Hatano, Taku, Sahara, Naruhiko, Suhara, Tetsuya, Higuchi, Makoto, and Hattori, Nobutaka

Abstract

BACKGROUND: While mechanistic links between tau abnormalities and neurodegeneration have been proven in frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, variability of the tau pathogenesis and its relation to clinical progressions in the same MAPT mutation carriers are yet to be clarified. OBJECTIVES: The present study aimed to analyze clinical profiles, tau accumulations, and their correlations in 3 kindreds with frontotemporal dementia and parkinsonism linked to chromosome 17 attributed to the MAPT N279K mutation. METHODS: Four patients with N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT underwent [11 C]PBB3-PET to estimate regional tau loads. RESULTS: Haplotype assays revealed that these kindreds originated from a single founder. Despite homogeneity of the disease-causing MAPT allele, clinical progression was more rapid in 2 kindreds than in the other. The kindred with slow progression showed mild tau depositions, mostly confined to the midbrain and medial temporal areas. In contrast, kindreds with rapid progression showed profoundly increased [11 C]PBB3 binding in widespread regions from an early disease stage. CONCLUSIONS: [11 C]PBB3-PET can capture four-repeat tau pathologies characteristic of N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT. Our findings indicate that, in addition to the mutated MAPT allele, genetic and/or epigenetic modifiers of tau pathologies lead to heterogeneous clinicopathological features. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Published
2019

39. JCB899577 Supplemental Material - Supplemental material for Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia

Author

Naohide Kurita, Yamashiro, Kazuo, Kuroki, Takuma, Tanaka, Ryota, Urabe, Takao, Ueno, Yuji, Nobukazu Miyamoto, Takanashi, Masashi, Shimura, Hideki, Inaba, Toshiki, Yamashiro, Yuichiro, Nomoto, Koji, Matsumoto, Satoshi, Takahashi, Takuya, Tsuji, Hirokazu, Asahara, Takashi, and Hattori, Nobutaka

Subjects
110320 Radiology and Organ Imaging, FOS: Clinical medicine, FOS: Biological sciences, Medicine, Cell Biology, 110305 Emergency Medicine, 110306 Endocrinology, Biochemistry, 69999 Biological Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, JCB899577 Supplemental Material for Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia by Naohide Kurita, Kazuo Yamashiro, Takuma Kuroki, Ryota Tanaka, Takao Urabe, Yuji Ueno, Nobukazu Miyamoto, Masashi Takanashi, Hideki Shimura, Toshiki Inaba, Yuichiro Yamashiro, Koji Nomoto, Satoshi Matsumoto, Takuya Takahashi, Hirokazu Tsuji, Takashi Asahara and Nobutaka Hattori in Journal of Cerebral Blood Flow & Metabolism

Published
2020
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46. Visual Grasping in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 (Microtubule-Associated with Protein Tau): A Comparison of N-Isopropyl-p-[123I]-Iodoamphetamine Brain Perfusion Single Photon Emission Computed Tomography Analysis with Progressive Supranuclear Palsy

Author

Ogaki, Kotaro, Motoi, Yumiko, Li, Yuanzhe, Tomiyama, Hiroyuki, Shimizu, Natsue, Takanashi, Masashi, Nakanishi, Atsushi, Yokoyama, Kazumasa, and Hattori, Nobutaka

Published
2011
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47. Age-Associated Insolubility of Parkin in Human Midbrain is Linked to Redox Balance and Sequestration of Reactive Dopamine Metabolites

Author

Tokarew, Jacqueline M., primary, El-Kodsi, Daniel N., additional, Lengacher, Nathalie A., additional, Fehr, Travis K., additional, Nguyen, Angela P., additional, Shutinoski, Bojan, additional, O’Nuallain, Brian, additional, Jin, Ming, additional, Khan, Jasmine M., additional, Ng, Andy C. H., additional, Li, Juan, additional, Jiang, Qiubo, additional, Zhang, Mei, additional, Wang, Liqun, additional, Sengupta, Rajib, additional, Barber, Kathryn R., additional, Tran, An, additional, Zandee, Stephanie, additional, Dong, Xiajun, additional, Scherzer, Clemens R., additional, Prat, Alexandre, additional, Tsai, Eve, additional, Takanashi, Masashi, additional, Hattori, Nobutaka, additional, Chan, Jennifer A., additional, Zecca, Luigi, additional, West, Andrew B., additional, Holmgren, Arne, additional, Puente, Lawrence, additional, Shaw, Gary S., additional, Toth, Gergely, additional, Woulfe, John M., additional, Taylor, Peggy, additional, Tomlinson, Julianna J., additional, and Schlossmacher, Michael G., additional

Published
2020
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48. Systemic Sclerosis Precedes POEMS Syndrome

Author

Yamashita, Yuri, primary, Takahashi, Yoshihiro, additional, Tsunemi, Taiji, additional, Shirane, Shuichi, additional, Nakazato-Taniguchi, Tomoko, additional, Taniguchi, Daisuke, additional, Takanashi, Masashi, additional, Sasaki, Makoto, additional, Komatsu, Norio, additional, and Hattori, Nobutaka, additional

Published
2020
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