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| 1 | Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection显示文摘Missense mutations in Leucine-Rich Repeat Kinase 2(LRRK2)cause the majority of familial and some sporadic forms of Parkinson’s disease(PD).The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity,promoting the development of LRRK2 kinase inhibitors as therapeutics.Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise.However,nearly all inhibitors are ATP competitive—some with unwanted side effects and unclear clinical outcome—alternative types of LRRK2 inhibitors are lacking.Herein we identify 5′-deoxyadenosylcobalamin(AdoCbl),a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity.Multiple assays show that AdoCbl directly binds LRRK2,leading to the alterations of protein conformation and ATP binding in LRRK2.STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain.Furthermore,we provide evidence that AdoCbl modulates LRRK2 activity through disrupting LRRK2 dimerization.Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue,and prevents neurotoxicity in cultured primary rodent neurons as well as in transgenic C.elegans and D.melanogaster expressing LRRK2 disease variants.Finally,AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models.Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism,which can be harnessed to develop new LRRK2-based PD therapeutics in the future. | Adam Schaffner Xianting Li Yacob Gomez-Llorente Emmanouela Leandrou Anna Memou Nicolina Clemente Chen Yao Farinaz Afsari Lianteng Zhi Nina Pan Keita Morohashi Xiaoluan Hua Ming-Ming Zhou Chunyu Wang Hui Zhang Shu G.Chen Christopher J.Elliott Hardy Rideout Iban Ubarretxena-Belandia Zhenyu Yue | 2019 | Cell Research2019，29，4： | 7 |
| 2 | Trace element levels in adults from the west coast of C-nada and associations with age,gender,diet,activities and levels of other trace elements显示文摘 | CLARK N A TESCHKE K RIDEOUT K | 2007 | Chemosphere2007，70，1： | 1 |
| 3 | Antimicrobial sesquiterpenoids and diarylheptanoid from Curcuma domestica显示文摘 | Ragasa C Y Laguardiaand M A Rideout J A | 2005 | Chem Res Commun2005，18，1： | 1 |
| 4 | Epigenetic instability in ES cells and cloned mice显示文摘 | Humpherys D Eggan K Akutsu H Hochedlinger K Rideout WM 3rd Biniszkiewicz D | 2001 | Science2001，293，5527： | 1 |
| 5 | Changes in ratio of soluble sugars and free amino nitrogen in the apical meristem during floral transition of tobacco 显示文摘 | Rideout J Raper J Miner G | 1992 | International Journal of Plant Sciences1992，153，1： | 1 |
| 6 | Generation of mice from wild-type and targeted ES cells by nuclear cloning 显示文摘 | Rideout W M Wakayama T Wutz A | 2000 | Nat Genet2000，，24： | 1 |
| 7 | Developmental potential of mouse primordial germ cells 显示文摘 | Kato Y Rideout WM 3rd Hilton K | 1999 | Development1999，126，9： | 1 |
| 8 | Proteasome inhibition and Parkinson' s disease modeling 显示文摘 | Bove J Zhou C Jackson-lewis V Taylor J Chu Y Rideout H J | 2006 | Ann Neurol2006，60，： | 1 |
| 9 | Nuclear cloning and epigenetic reprogramming of the genome显示文摘 | Rideout WM Eggan K Jaenisch R | 2001 | Science2001，293，5532： | 1 |
| 10 | Ionone derivatives from Alternanthera sessilis显示文摘 | Ragasa C Y Tremor N Rideout J A | 2002 | Journal of Asian Natural Produbts Research2002，4，2： | 1 |
| 11 | Proteasomal inhibitionleads to formation of ubiquitin/alpha synuclein immunoreac- tive inclusions in PC12 cells显示文摘 | Rideout HJ Larsen KE Sulzer D | 2001 | J Neurochem2001，78，4： | 1 |
| 12 | Proteasomal inhibition leads to formation of ubiquitin/alpha-synuclein-immunoreactive inclusions in PC12 cells 显示文摘 | Rideout H J Larsen K E Sulzer D | 2001 | J Neurochem2001，78，4： | 1 |
| 13 | Trace element levels in adults from the west coast of Canada and associations with age,gender,diet,activities,and levels of other trace elements显示文摘 | CLARK N A TESCHKE K RIDEOUT K | 2007 | Chemosphere2007，70，1： | 1 |
| 14 | Development of an instrument to assess individual student performance in small group tutorials显示文摘 | Michael G Ladouceur Elizabeth M Rideout Margaret EA Black | 2004 | Journal of Nursing Education2004，43，10： | 1 |
| 15 | Analytical target cascading in automotive design显示文摘 | KIM H M RIDEOUT D G PAPALAMBROS P Y | 2003 | ASME Journal of Mechanical Design2003，125，3： | 1 |
| 16 | Caspase inhibition: a potential therapeutic strategy in neurological diseases显示文摘 | Rideout HJ Stefanis L | 2001 | Histol Histopathol2001，16，3： | 1 |
| 17 | Nuclear cloning and epigenetic reprogramming of the genome 显示文摘 | Rideout WM 3rd Eggan K Jaenisch R | 2001 | Science2001，293，5532： | 1 |
| 18 | Trace ele- ment levels in adults from the west coast of Canada and associations with age, gender, diet, activities, and levels of other trace elements显示文摘 | Clark NA Teschke K Rideout K | 2007 | Chemosphere2007，70，1： | 1 |
| 19 | Subsampledopen-reference clustering creates consistent, comprehensive OTUdefinitions and scales to billions of sequences 显示文摘 | Rideout JR He Y Navas-Molina JA | 2014 | PeerJ2014，2，： | 1 |
| 20 | Antineo- plastic activity, synergism, and antagonismof triarylal- kylphosphonium salts and their combinations 显示文摘 | Patel J Rideout D McCarthy M R | 1994 | Anti- cancer Res1994，14，1： | 1 |
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