Mechanisms of Transmission of Pathological Alpha-Synuclein in Neurons
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Virginia M.-Y. Lee, PhD Project Leader |
Project Description
This project will test the hypothesis that neurons from different CNS regions are selectively vulnerable to develop either LBs/LNs alone or LBs/LNs with AD-like tau pathology and altered levels of secreted Abeta in response totreatment with distinct a-syn PFF strains.
The project will generate and characterize synthetic a-syn PFFs strains that differentially modulate the LBs/LNs and AD pathology and will determine if 
enriched LBs/LNs fractions isolated from different regions of PD/PDD/DLB brains, will differentially “seed” and “cross-seed” the recruitment of endogenous a-syn and tau into insoluble aggregates in primary neurons, thus reflecting strain-like properties..
Lastly, the project will collaborate with Project IV to identify anti-a-syn monoclonal antibodies (MAbs) that block a-syn transmission in neuron-based synucleinopathy models to be used for immunotherapy in a-syn Tg mice of Project IV.
Publications
- Lippa, CF, Duda, JE, Grossman, M, Hurtig, H, Aarsland, D, Boeve, B, Brooks, DJ, Dickson, DW, Dubois, B, Emre, M, Fahn, S, Farmer, J, Galasko, D., Galvin, JE, Goetz, C, Growdon, JH, Gwinn-Hardy, KA, Hardy, J, Heutink, P, Iwatsubo, T, Kosaka, K, Lee, VM-Y, Leverenz, J, Masliah, E, McKeith, IE, Nussbaum, RL, Olanow, CW, Ravina, BM, Singleton, AB, Tanner, CM, Trojanowski, JQ, Wszolek, ZK., DLB/PDD Working Group. DLB and PDD boundary issues: Diagnosis, treatment, molecular pathology and biomarkers. Neurol., 68:812-819, 2007.
- Luk, CK, Hyde, EG, Trojanowski, JQ, Lee, VM-Y. Sensitive fluorescence polarization technique for rapid screening of alpha-synuclein oligomerization/ fibrillization inhibitors. Biochemistry, 46:12522-12529, 2007.
- Murray, R, Neumann, M, Forman, MS, Farmer, J, Massimo, L, Rice, A, Miller, BL, Johnson, JK, Clark, CM, Hurtig, HI, Gorno-Tempini ML, Lee, VM-Y, Trojanowski, JQ, Grossman, M. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology, 68:1274-1283, 2007.
- Nakashima-Yasuda, H, Uryu, K, Robinson, J, Xie, SX, Hurtig, H, Duda, J, Arnold, SE, Siderowf, A, Grossman, M, Leverenz, JB, Lopez, O, Hamilton, R, Tsuang, DW, Galasko, D, Masliah, E, Kaye, J, Woltjer, R, Clark, CM, Montine, TJ, Lee, VM -Y, Trojanowski, JQ. Co-morbidity of TDP-43 Proteinopathy in Lewy body diseases. Acta Neuropathol., 114:221-229, 2007.
- Roy, S, Winton, MJ, Black, MM, Trojanowski, JQ, Lee, VM-Y. Rapid and intermittent co-transport of slow component-b proteins. J. Neurosci., 27:3131-3138, 2007.
- Shaw, LM, Korecka, M, Clark, CM, Lee, VM-Y, Trojanowski, JQ. Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nat. Rev. Drug Discovery, 6:295-303, 2007.
- Skovronsky, D, Lee, VM-Y, Trojanowski, JQ. Tau in parkinsonian diseases. In: Parkinson’s Disease: Genetics And Pathogenesis, T. Dawson (Ed.), Marcel Dekker, New York, NY, pp: 187-198, 2007. Pdf
- Soper, J, Trojanowski, JQ, Lee, VM-Y. Alpha-synuclein in Parkinson’s disease. In: Parkinson’s Disease: Genetics And Pathogenesis, T. Dawson (Ed.), Marcel Dekker, New York, NY, pp:167-186, 2007.
- Chen-Plotkin, A, Yuan, W, Anderson, C, McCarty-Wood, E, Hurtig, HI, Clark, CM, Miller, BL, Lee, VM-Y, Trojanowski, JQ, Grossman, M, Van Deerlin, V. Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations. Neurol., 70:52-527, 2008.
- Geser, F, Winton, MJ, Kwong, LK, Xu, Y, Xie, SX, Igaz, LM, Garruto, R, Perl, D, Galasko, D, Lee, VM-Y, Trojanowski, JQ. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropath., 115:133-145, 2008.
- Soper JH, Roy, S, Steiber A, Lee, E, Wilson, RB, Trojanowski JQ, Burd, CG, Lee VMY. α-Synuclein Induced Aggregation of Cytoplasmic Vesicles in S. cerevisiae. Mol. Biol. Cell 19:1093-1103, 2008. PMC2262993
- Gao, HM, Kotzbauer, PT, Uryu, K, Trojanowski, JQ, Lee, VM-Y. Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J. Neurosci., 28:7687-7698, 2008. PMC2702093
- Luk, CK, Mills, IP, Trojanowski, JQ, Lee, VM-Y. Interactions between Hsp70 and the hydrophobic core of alpha-synuclein inhibit fibril assembly. Biochemistry, 47:12614-12625, 2008 PMC2648307
- Roy, S, Lee, VM-Y, and Trojanowski, JQ. Axonal transport and neurodegenerative diseases. In: Encyclopedia Of Neuroscience, L.R. Squire (Ed.), Vol. 1, Oxford Academic Press, pp. 1199-1203, 2009.
- Roy, S, Winton, MJ, Black, MM, Trojanowski, JQ, Lee, VM-Y. Cytoskeletal requirements in axonal transport of slow component-b. J. Neurosci., 28:5248-5256, 2008. PMC2648304
- Trojanowski, JQ, Forman, MS, Lee, VM-Y. Alzheimer’s disease, Parkinson’s disease and frontotemporal dementias: Different manifestations of protein misfolding. In: Advances In Alzheimer’s And Parkinson’s Disease. A. Fisher, M. Memo, F. Stocchi, I. Hanin, (Eds.), Springer Science, New York, NY, Vol. 37, pp. 123-133, 2008.
- Luk, KC, Song, C, O’Brien, P, Stieber, A, Branch, J, Brunden, KR, Trojanowski, JQ, Lee, VM-Y. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Nat. Acad. Sci., 106:20051-20056, 2009. PMC2785290
- Roy, S, Lee, VM-Y, and Trojanowski, JQ. Axonal transport and neurodegenerative diseases. In: Handbook Of The Neuroscience Of Aging, P.R. Hof, and C.V. Mobbs (Eds.), Elsevier Academic Press, pp. 107-112, 2009.
- Arnold, SE, Lee, E, Moberg, PJ, Stutzbach, L, Kazi, H, Han, L-Y, Lee, VM-Y, Trojanowski, JQ. Aβ and PHFtau pathology in olfactory epithelium is increased in Alzheimer’s disease and correlates with brain pathology. Ann. Neurol., 67:462-469, 2010. PMC2864948
- Lim, Y, Kehm, V, Li, C, Trojanowski, JQ, Lee, V M-Y. Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption. Exper. Neurol., 221:86-97, 2010. PMC2812632
- Soper, JH, Kehm, V, Burd, CG, Bankaitis, V.A, Lee, VM-Y. Aggregation of alpha-Synuclein in S. cerevisias is associated with defects in endosomal trafficking and phospholipid biosynthesis. J Mol Neurosci (Epub ahead of print), 2010. PMC3147281
- Hu, WT, Chen-Plotkin, A, Arnold, SE, Grossman, M, Clark, CM, Shaw, LM, McCluskey, L, Elman, LB, Karlawish, J, Hurtig, HI, Siderowf, A, Lee, VM-Y, Soares, HD, Trojanowski, JQ. Biomarker discovery for Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease. Acta Neuropathol 120:385-399, 2010. PMC2982700
- Chen-Plotkin, AS, Hu, WT, Siderowf, A, Weintraub, D, Goldman Gross, R, Hurtig, HI, Xie, SX, Arnold , SE, Grossman, M, Clark, CM, Shaw, LM, McCluskey, L, Elman, L, Van Deerlin, VM, Lee, VM-Y, Soares, H, Trojanowski, JQ. Plasma EGF levels correlate with cognitive performance and predict cognitive decline in Parkinson’s Disease. Ann Neurol, 69: 655-663, 2011. PMC3155276
- Soper, JH, Kehm, V, Burd, CG, Bankaitis, VA and Lee, VM-Y. Aggregation of alpha-Synuclein in S. cerevisias is associated with defects in endosomal trafficking and phospholipid biosynthesis. J Mol Neurosci 43:391-405, 2011 PMC3147281
- Lim, Y, Kehm, V, Lee, EB, Soper, JH, Li, C, Trojanowski, JQ, Lee, VM-Y. α-syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy Bodies. J. Neurosci. 31:10076-87, 2011 PMC3144489
- Volpicelli-Daley, LA, Luk, KC, Patel, TP, Tanik, SA, Riddle, DM, Stieber, A, Meany DF, Trojanowski, JQ, Lee VM-Y. Exogenous α-synuclein fibrils initiate propagation of Lewy neurite and Lewy body-like pathology that leads to synaptic dysfunction and neuron death. Neuron, 72: 57-71, 2011 PMC3204802
- Wang, Y, Shi, M, Chung, KA, Zabetian, CP, Leverenz, JB, Berg, D, Srulijes, K, Trojanowski, JQ, Lee, VM-Y, Siderowf, AD, Hurtig, H, Litvan, I, Schiess, MC, Peskind, ER, Masuda, M, Hasegawa, M, Lin, X, Pan, C, Galasko, D, Goldstein, DS, Jensen, PH, Yang, H, Cain, KC, Zhang, J. Phosphorylated α-synuclein in Parkinson disease and related parkinsonism. Sci. Transl. Med., In press, 2012.
- Luk, KC, Kehm, VN, Zhang, B, O’Brien, P, Trojanowski, JQ, Lee VM-Y. Intracerebral α-synuclein fibril injection initiates rapid progressive neurodegeneration in a transgenic mouse model of α-synucleinopathies. J. Exper. Med., In press, 2012.