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.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
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