Darren J. Moore, Laboratory of Molecular Neurodegenerative Research: The goal of our research is to understand the molecular basis of neurodegeneration as it pertains to the common neurodegenerative movement disorder, Parkinson’s disease (PD) and related disorders. Our research focuses on investigating the normal cell biology and pathophysiology of gene products associated with rare familial forms of PD, including the leucine-rich repeat kinase 2 (PARK8), parkin (PARK2) and ATP13A2 (PARK9) proteins. Our studies aim to develop relevant disease models using a combination of transgenic/knockout mice, primary neuronal cultures, baker’s yeast and human brain tissue in which to probe the molecular and cellular mechanisms and/or pathways through which disease-associated variants in these proteins induce neuronal dysfunction and neurodegeneration. Through molecular, biochemical and cellular studies of these familial gene products we hope to gain important insight into the molecular pathogenesis of the common sporadic, idiopathic form of this disease. Furthermore, we aim to employ a translational approach to exploit our observations in order to test and develop novel therapeutic strategies to alleviate disease. Our central mission is to understand and model the molecular pathogenesis of PD and related neurodegenerative diseases so that we can eventually develop novel targeted therapies and neuroprotective strategies to treat or prevent these devastating diseases.

Abumrad NA, Moore DJ. Parkin reinvents itself to regulate fatty acid metabolism by tagging CD36. J. Clin. Invest. 2011, 121:3389-92.

Trancikova A, Tsika E, Moore DJ. Mitochondrial dysfunction in genetic animal models of Parkinson’s disease. Antioxid. Redox Signal. 2011, Epub Oct. 4.

Glauser L, Sonnay S, Stafa K, Moore DJ. Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J. Neurochem. 2011, 118: 636-45.

Ramonet D, Daher JPL, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 2011, 6: e18568.

Higashi S, Moore DJ, Minegishi M, Kasanuki K, Fujishiro H, Kabuta T, Togo T, Katsuse O, Uchikado H, Furukawa Y, Hino H, Kosaka K, Sato K, Arai H, Wada K, Iseki E. Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies. J. Neuropathol. Exp. Neurol. 2011, 70: 264-80.

Trancikova A, Ramonet D, Moore DJ. Genetic mouse models of neurodegenerative diseases. Prog. Mol. Biol. Trans. Sci. 2011, 100: 419-82.

Dusonchet J, Kochubey O, Stafa K, Young SM, Zufferey R, Moore, DJ, Schneider BL, Aebischer, P. A rat model of progressive nigral neurodegeneration induced by the Parkinson’s disease-associated G2019S mutation in LRRK2. J. Neurosci. 2011, 31(3): 907-12.

Li X, Moore DJ, Xiong Y, Dawson TM, Dawson VL. Re-evaluation of phosphorylation sites in the Parkinson’s disease-associated leucine-rich repeat kinase 2. J. Biol. Chem. 2010, 285: 29569-76.

Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, Bowers WJ, Dawson VL, Dawson TM, Moore DJ. GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genetics 2010, 6(4):e1000902.

Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, May J, Tocilescu MA, Liu W, Ko HS, Magrane J, Moore DJ, Dawson VL, Grailhe R, Dawson TM, Li C, Tieu K, Przedborski S. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl. Acad. Sci. U. S. A. 2009, 107: 378-83.

Higashi S, Moore DJ, Yamamoto R, Minegishi M, Sato K, Togo T, Katsuse O, Uchikado H, Furukawa Y, Hino H, Kosaka K, Emson PC, Wada K, Dawson VL, Dawson TM, Arai H, Iseki E. Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in Lewy body disease. J. Neuropathol. Exp. Neurol. 2009, 68: 994-1005.

Daher, JPL, Ying, M, Banerjee, R, McDonald, RS, Hahn, MD, Yang, L, Beal, MF, Thomas, B, Dawson, VL, Dawson, TM, Moore, DJ. Conditional transgenic mice expressing C-terminally truncated human alpha-synuclein (Syn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons. Mol. Neurodegeneration (2009) 4:34.

Higashi, S, Moore, DJ, Yamamoto, R, Minegishi, M, Sato, K, Togo, T, Katsuse, O, Uchikado, H, Furukawa, Y, Hino, H, Kosaka, K, Emson, PC, Wada, K, Dawson, VL, Dawson, TM, Arai, H, Iseki, E. Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in Lewy body disease. J. Neuropathol. Exp. Neurol. (2009) 68(9), 994-1005.

Dawson, TM, Moore, DJ, West, AB. Revelations and revolutions in the understanding of Parkinson´s disease. Biochim. Biophys. Acta (2009) 1792, 585-6.

Ko, HS, Bailey, R, Smith, WW, Liu, Z, Shin, J-H, Lee, Y-I, Zhang, Y-J, Jiang, H, Ross, CA, Moore, DJ, Patterson, C, Petrucelli, L, Dawson, TM, Dawson, VL. CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation and toxicity. Proc. Natl. Acad. Sci. U.S.A. (2009) 106, 2897-902.

Moore, DJ, Dawson, TM. Value of Genetic Models in Understanding the Cause and Mechanisms of Parkinson´s Disease. Curr. Neurol. Neurosci. Rep. (2008), 8, 288-96.

Moore, DJ. The Biology and Pathobiology of LRRK2: Implications for Parkinson´s Disease. Parkinsonism Relat. Disord., (2008), 14, S92-98. 

Moore, DJ, West, AB, Dikeman, DA, Dawson, VL, Dawson, TM. Parkin mediates the degradation-independent ubiquitination of Hsp70. J. Neurochem. (2008) 105, 1806-19.

Biskup, S, Moore, DJ, Rea, A, Lorenz-Deperieux, B, Coombes, CE, Dawson, VL, Dawson, TM, West, AB. Dynamic and Redundant Regulation of LRRK2 and LRRK1 Expression. BMC Neurosci. (2007) 8, 102. 

Higashi, S, Biskup, S, West, AB, Trinkaus, D, Dawson, VL, Faull, RLM, Waldvogel, HJ, Arai, H, Dawson, TM, Moore, DJ*, Emson, PC*. Localization of Parkinson´s disease-associated LRRK2 in normal and pathological human brain. Brain Res. (2007) 1155, 208-19. (*Authors contributed equally) 

West, AB, Moore, DJ, Choi, C, Andrabi, SA, Li, X, Dikeman, D, Biskup, S, Zhang, Z, Lim, KL, Dawson, VL, Dawson, TM. Parkinson´s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet. (2007) 16, 223-32.

Higashi, S, Moore, DJ, Colebrooke, RE, Biskup, S, Dawson, VL, Arai, H, Dawson, TM, Emson, PC. Expression and localization of Parkinson´s disease-associated leucine-rich repeat kinase 2 in the mouse brain. J. Neurochem. (2007) 100, 368-81. 

Moore, DJ. Parkin: a multifaceted ubiquitin ligase. Biochem. Soc. Trans. (2006) 34, 749-53. 

Biskup, S, Moore, DJ. Detrimental deletions: mitochondria, aging and Parkinson´s disease. BioEssays (2006) 28, 963-7.

Biskup, S*, Moore, DJ*, Celsi, F, Higashi, S, West, AB, Andrabi, SA, Kurkinen, K, Yu, SW, Savitt, JM, Waldvogel, HJ, Faull, RL, Emson, PC, Torp, R, Ottersen, OP, Dawson, TM, Dawson, VL. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann. Neurol. (2006) 60, 557-69. (*Authors contributed equally). 

Moore, DJ, Dawson, VL, Dawson, TM. Lessons from Drosophila models of DJ-1 deficiency. Sci. Aging. Knowl. Environ. (2006) 2, pe2. 

Smith, WW, Pei, Z, Jiang, H, Moore, DJ, Liang, Y, West, AB, Dawson, VL, Dawson, TM, Ross, CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl. Acad. Sci. U.S.A. (2005) 102, 18676-81. 

West, AB*, Moore, DJ*, Biskup, S, Bugayenko, A, Smith, WW, Ross, CA, Dawson, VL, Dawson, TM. Parkinson´s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. U.S.A. (2005) 102, 16842-7. (*Authors contributed equally). 

Moore, DJ, West, AB, Dawson, VL, Dawson, TM. Molecular pathophysiology of Parkinson´s disease. Annu. Rev. Neurosci. (2005) 28, 57-87.

Zhang, L, Shimoji, M, Thomas, B, Moore, DJ, Yu, SW, Marupudi, NI, Torp, R, Torgner, IA, Ottersen, OP, Dawson, TM, Dawson, VL. Mitochondrial localization of the Parkinson´s disease-related protein DJ-1: Implications for pathogenesis. Hum. Mol. Genet. (2005) 14, 2063-73. 

Moore, DJ, Zhang, L, Troncoso, J, Lee, MK, Hattori, N, Mizuno, Y, Dawson, TM, Dawson, VL. of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum. Mol. Genet. (2005) 14, 71-84. 

Moore, DJ, Dawson, VL, Dawson, TM. Genetics of Parkinson´s disease: what do mutations in DJ-1 tell us? Ann. Neurol. (2003) 54, 281-82. 

Moore, DJ, Dawson, VL, Dawson, TM. Role for the ubiquitin-proteasome system in Parkinson´s disease and other neurodegenerative brain amyloidoses. NeuroMolecular Med. (2003) 4, 95-108. 

Moore, DJ, Zhang, L, Dawson, TM, Dawson, VL. A missense mutation (L166P) in DJ-1, linked to familial Parkinson´s disease, confers reduced protein stability and impairs homo-oligomerization. J. Neurochem. (2003) 87, 1558-67.

Transgenesis/Gene targeting
Mouse models/genetics
Neuronal cell biology
Yeast genetics/biology