Co-Director and ITN Scholar, Center for Neurodegenerative Disease, Institute for Translational Neuroscience (http://itn.umn.edu/)
My group is using transgenic mouse models to study the mechanisms of human neurodegenerative diseases, particularly AD and PD. There are three broad areas of active interest. 1) Understanding the pathogenesis/progression of PD using alpha-synuclein and LRRK2 transgenic mouse models. 2) Mechanisms of amyloid-dependent neurodegeneration using transgenic mouse models of AD. 3) Pathologic interactions between genetic and environmental factors. While most cases of AD and PD are “sporadic”, the key assumption is that genetic lesions that cause classic forms of the relevant neurodegenerative diseases will cause neural abnormalities that are common between the genetic and sporadic forms of the disease. When used in conjunction with careful analysis of human subjects, invertebrate models, and cell culture models, we will be able to define mechanisms that are directly relevant to the pathogenesis and identify possible targets for therapeutic intervention. The models generated are also essential for cross-platform screening and validation of novel therapeutic approaches. My group has identified several robust biochemical, pathological and behavioral outcome measures in transgenic mouse models of AD and PD. These measures will be essential for in vivo preclinical evaluation of therapeutics.
Parkinson's Disease (PD)
Genetic and biochemical abnormalities of a-synuclein (a-Syn) and LRRK2 are directly relevant to the pathogenesis of PD. My group has contributed to the field by generating a human a-Syn transgenic (Tg) mouse model of a-synucleinopathy, characterizing the pathological abnormalities associated with the disease, and characterizing the cell biology of a-Syn. We are currently studying the role of protein folding pathways, mitochondrial abnormalities, oxidative stress, inflammation, and aberrant protein kinase regulation.
Alzheimer's Disease (AD)
My laboratory was first to describe progressive degeneration of monoaminergic (MAergic) neurons (5-HT, NE) in mouse model of AD. Significantly, degeneration 5-HT and NE systems is associated with human AD. Our findings will provide a platform to study the mechanisms of amyloid-dependent neurodegeneration in vivo and will provide an ideal in vivo model system to evaluate neuroprotective therapies. We are currently testing if the degeneration of 5-HT and NE system participates in progression of amyloid pathology, progression of cognitive dysfunction, and development of non-cognitive abnormalities. Mechanistically, we are evaluating if abnormal BDNF signaling is involved in monoaminergic neurodegeneration.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Adibi JJ, Lee MK, Naimi AI, Barrett E, Nguyen RH, Sathyanarayana S, Zhao Y, Thiet MP, Redmon JB, Swan SH. Human Chorionic Gonadotropin Partially Mediates Phthalate Association With Male and Female Anogenital Distance. J Clin Endocrinol Metab. 2015 Sep;100(9):E1216-24.
Zhao L, Hadziahmetovic M, Wang C, Xu X, Song Y, Jinnah HA, Wodzinska J, Iacovelli J, Wolkow N, Krajacic P, Cwanger Weissberger A, Connelly J, Spino M, Lee MK, Connor J, Giasson B, Harris ZL, Dunaief JL. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem. 2015 Aug 25.
Griffin P, Sexton A, Macneill L, Iizuka Y, Lee MK, Bazzaro M. Method for measuring the activity of deubiquitinating enzymes in cell lines and tissue samples. J Vis Exp. 2015 May 10;(99):e52784.
Brahmbhatt A, NievesTorres E, Yang B, Edwards WD, Roy Chaudhury P, Lee MK, Kong H, Mukhopadhyay D, Kumar R, Misra S. The role of Iex-1 in the pathogenesis of venous neointimal hyperplasia associated with hemodialysis arteriovenous fistula. PLoS One. 2014 Jul 18;9(7):e102542.
Loth DW, Artigas MS, Gharib SA, Wain LV, Franceschini N, Koch B, Pottinger TD, Smith AV, Duan Q, Oldmeadow C, Lee MK, Strachan DP, James AL, Huffman JE, Vitart V, Ramasamy A, Wareham NJ, Kaprio J, Wang XQ, Trochet H, Kähönen M, Flexeder C, Albrecht E, Lopez LM, de Jong K, Thyagarajan B, Alves AC, Enroth S, Omenaas E, Joshi PK, Fall T, Viñuela A, Launer LJ, Loehr LR, Fornage M, Li G, Wilk JB, Tang W, Manichaikul A, Lahousse L, Harris TB, North KE, Rudnicka AR, Hui J, Gu X, Lumley T, Wright AF, Hastie ND, Campbell S, Kumar R, Pin I, Scott RA, Pietiläinen KH, Surakka I, Liu Y, Holliday EG, Schulz H, Heinrich J, Davies G, Vonk JM, Wojczynski M, Pouta A, Johansson A, Wild SH, Ingelsson E, Rivadeneira F, Völzke H, Hysi PG, Eiriksdottir G, Morrison AC, Rotter JI, Gao W, Postma DS, White WB, Rich SS, Hofman A, Aspelund T, Couper D, Smith LJ, Psaty BM, Lohman K, Burchard EG, Uitterlinden AG, Garcia M, Joubert BR, McArdle WL, Musk AB, Hansel N, Heckbert SR, Zgaga L, van Meurs JB, Navarro P, Rudan I, Oh YM, Redline S, Jarvis DL, Zhao JH, Rantanen T, O'Connor GT, Ripatti S, Scott RJ, Karrasch S, Grallert H, Gaddis NC, Starr JM, Wijmenga C, Minster RL, Lederer DJ, Pekkanen J, Gyllensten U, Campbell H, Morris AP, Gläser S, Hammond CJ, Burkart KM, Beilby J, Kritchevsky SB, Gudnason V, Hancock DB, Williams OD, Polasek O, Zemunik T, Kolcic I, Petrini MF, Wjst M, Kim WJ, Porteous DJ, Scotland G, Smith BH, Viljanen A, Heliövaara M, Attia JR, Sayers I, Hampel R, Gieger C, Deary IJ, Boezen HM, Newman A, Jarvelin MR, Wilson JF, Lind L, Stricker BH, Teumer A, Spector TD, Melén E, Peters MJ, Lange LA, Barr RG, Bracke KR, Verhamme FM, Sung J, Hiemstra PS, Cassano PA, Sood A, Hayward C, Dupuis J, Hall IP, Brusselle GG, Tobin MD, London SJ. Genome-wide association analysis identifies six new loci associated with forced vital capacity. Nat Genet. 2014 Jul;46(7):669-77.
Coughlin K, Anchoori R, Iizuka Y, Meints J, MacNeill L, Vogel RI, Orlowski RZ, Lee MK, Roden RB, Bazzaro M. Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Clin Cancer Res. 2014 Jun 15;20(12):3174-86.
Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC, Iwatsubo T, Schneider BL, Lee MK. (2012) Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. ?J Neurosci.,32: 3306-3320. This Week in Journal (TWIJ) featured article.
Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, Lee MK. (2012). Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J Neurosci., ?32: 3301-3305.
Tuite PJ, Mangia S, Tyan A, Lee MK, Garwood M, Michaeli S. (2012) Magnetization Transfer and adiabatic R1<rho> MRI in the brainstem of Parkinson's disease.? Parkinsonism and Related Disorders. 2012 [Epub ahead of print].
Thomas B, Mandir A, Garay J, West N, Liu Y, Andrabi S, Stirling W, Dawson V, Dawson T, Lee MK. (2011) Resistance to MPTP-neurotoxicity in α-synuclein knockout mice is complemented by human α-synuclein and is associated with increased β-synuclein and Akt activation.? PLoS One, 2011, 6:e16706.
Liu Y, Lee MK*, James M, Price DL, Borchelt DR, Troncoso JC, and Oh ES*. (2011) Passive Abeta immunotherapy attenuates monoaminergic axonal degeneration in the APPswe/PS1 mice. J Alzheimers’s Disease, 23:271-279. *Co-corresponding authors.
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH. (2010) Increased? expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.? Neuron, 65:66-79.??
Yang Y, She H, Gearing M, Colla E, Lee M, Shacka JJ, Mao Z. (2009) Regulation of Neuronal Survival Factor MEF2D by Chaperone-Mediated Autophagy. Science, 323:124-127.?
Liu Y, Yoo MJ, Savonenko A, Stirling W, Price DL, Borchelt DR, Mamounas L, Lyons WE, Blue M, Lee MK. (2008) Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer’s disease.? J Neurosci. 28:13805-14.
Wang J, Martin E, Gonzales V, Borchelt DR, Lee MK. (2008) Differential regulation of small heat shock proteins in transgenic mouse models of neurodegenerative diseases.?? Neurobiol. Aging 29:586-597.?
Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK. (2006) Parkinson’s Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death. J Neurosci. 26:41-50.?
Li W, West N, Colla E, Pletnikova O, Troncoso JC, Marsh L, Dawson TM, Jakala P, Hartman T, Price DL, Lee MK. (2005) Aggregation promoting C-terminal Truncation of α-synuclein is normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc. Natl. Acad. Sci. USA. 102:2162-2167.?
Li W, Lesuisse C, Xu Y, Troncoso J, Price D, Lee MK. (2004) Stabilization of alpha-synuclein polypeptide with aging and familial PD lined A53T mutation. J. Neurosci. 24:9400-9409.?
Lee MK*, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkin NA, Price DL. (2002)? Human a-Synuclein Harboring Familial Parkinson’s Disease Linked Ala53Thr Mutation Causes Neurodegenerative Disease with a-Synuclein Aggregation in Transgenic Mice.? Proc. Natl. Acad. Sci. USA.? 2002; 99:8968-8973.? *Corresponding Author