Animal Models of Parkinson's Dementia
|2010 Progress Report Update|
|Virginia M.-Y. Lee, PhD
This project tests hypotheses regarding mechanisms of alpha-synuclein toxicity and aggregate formation. Using postmortem human brain samples that are acquired and characterized in Core C, studies are conducted in this project to compare the regional distribution of alpha-synuclein, tau and A-beta neuropathology in clinically well-defined Parkinson's disease (PD), Parkinson's disease with dementia or Dementia with Lewy Bodies (PDD/DLB), and Lewy Body Variant of Alzheimer's disease (LBVAD) patients who have been followed longitudinally by Core B and studied by Projects 1 and 2.
New transgenic (TG) mouse models with regulated over expression of wild type (WT) or mutant human alpha-synuclein will be developed that target expression to telencephalon because existing alpha-synuclein TG mouse models have early onset motor deficits that do not model PDD/DLB. Thus, these TG mice will allow behavioral and molecular studies of novel models of PDD/DLB-like cognitive impairments linked to telencephalic accumulations of alpha-synuclein pathologies.
The role of regulated over expression of tau tangles and A-beta plaques in enhancing cognitive decline in the new alpha-synuclein TG mouse models will be evaluated, and comparisons of these TG mice with human disease samples from Core C will be performed to establish verisimilitude of these models to human synucleinopathies. Taken together, the work of Project 3 will lead to more informative models of synucleinopathies and address important questions on mechanisms leading to alpha-synuclein pathologies and their contribution to brain degeneration in synucleinopathies.
The studies from the past funding year advanced our understanding of mechanisms underlying neurodegenerative synucleinopathies. Significantly, the ongoing studies support the alpha-synuclein “transmission” hypothesis and we have established non-neuronal as well as neuronal cell-based assays and mouse models of transmission for the identification of potential therapies for PD.
- Luk, K.C., Song, C., O’Brien, P., Stieber, A., Branch, J., Brunden, K.R., Trojanowski, J.Q., and Lee, V.M.-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
- Lim, Y., Kehm, V., Li, C., Trojanowski, J.Q., and 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
- Roy, S., Lee, V.M.-Y., and Trojanowski, J.Q. 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.
- Fan Y, Limprasert P, Murray IVJ, Smith AC, Lee VM-Y, Trojanowski JQ, Sopher BL, La Spada AR. Beta-synuclein modulates alpha-synuclein neurotoxicity by reducing alpha-synuclein protein expression. Hum Molec Genet, 15:3002-3011, 2006.
- Lee VMY, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: New targets for drug discovery. Neuron, 52:33-38, 2006.
- Norris EH, Uryu K, Leight S, Giasson BI, Trojanowski JQ, Lee VM-Y. Oxidative damage by paraquat exacerbates neuropathology in an A53T transgenic mouse model of alpha-synucleinopathy. Am J Pathol, 170:658-666, 2007.
- Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O, Norris EH, Pham C-T, Yazawa I, Hilburger K, Miscenyi M, Giasson BI, Bonini NM, Lee VM-Y, Trojanowski JQ. Convergence of Hsp90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol, 168:947-961, 2006.