Immunotherapy Targeting Parkinson's Disease Transmission in Animal Models
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John Q. Trojanowski, MD, PhD Project Leader |
Project Description
The project will determine if unique synthetic a-syn PFF strains characterized by Project III differentially transmit LBD and cross-seed tau NFTs following injection into the brains of M83 mice, using methods established in our laboratory to assess behavior, neuropathology and cerebrospinal fluid (CSF) levels of a-syn and tau in these mice.
We will also determine if enriched fractions of LBs/LNs from PD substantia nigra (SN) versus PDD/DLB cingulate cortex (CC) contain distinct a-syn strains that differentially transmit LBD and cross-seed tau NFTs following injection into the brains of M83 mice using the same methods as in Aim 1.
Finally, we will conduct proof of concept (POC) studies in M83 mice injected with pathological a-syn to determine if immunization with monoclonal antibodies (MAbs), identified by Project III to neutralize a-syn transmission, abrogates induction and spread of a-syn pathology in vivo.
Publications
- Song, W-L, Lawson, JA, Reilly, D, Rokach, J, Giasson, B, and FitzGerald, GA. Neurofurans: novel indices of oxidant stress derived from docosahexaenoic acid. J. Biol. Chem. 283, 6-16, 2008.
- Waxman, EA, Duda, JE, Giasson, BI. Characterization of antibodies that selectively detect alpha-synuclein in pathological inclusions. Acta Neuropath. 116, 37-46, 2008. PMC2664556
- Waxman, EA, Giasson, BI. Specificity and regulation of casein kinase-mediated phosphorylation of alpha-synuclein. J. Neuropath. Exp. Neurol., 67,402-416, 2008. PMC2930078
- Covy, J P,Yuan, W, Waxman, EA, Hurtig, H I, Van Deerlin, V M, Giasson, BI. Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations. Mov. Disord. 24, 32-39, 2008. PMC2634827
- Giasson, BI, Van Deerlin, VM. Mutations in LRRK2 as a cause of Parkinson's disease. Neurosignals. 16:99-105, 2008.
- Covy, JP, Giasson, BI. Identification of compounds that inhibit leucine-rich repeat kinase 2. Biochem. Biophys. Res. Commun. 378, 473-477, 2009. PMC2633649
- Waxman, EA, Covy, JP, Bukh, I, Li, X, Dawson, TM, Giasson, B.I. Overexpression of leucine-rich repeat kinase 2 leads to aggresome-like formation, but it is not associated with alpha-synuclein aggregation or pathological inclusions. J. Neuropath. Exp. Neurol. 68, 785-796, 2009. PMC2722758
- Waxman, EA, Mazzulli, JR, Giasson, BI. Characterization of hydrophobic residue requirements for alpha-synuclein fibrillization. Biochemistry, 48, 9427-9436, 2009. PMC2758333
- Waxman, EA, Giasson, BI. Molecular mechanisms of alpha-synuclein neurodegeneration. Biochim. Biophys. Acta 1792, 616-624, 2009. PMC2756732
- Waxman, EA, Emmer, KL, Giasson, BI. Residues Glu83 plays a major role in negatively regulating alpha-synuclein amyloid formation. Biochem. Biophys. Res. Commun. 391, 1415-1420, 2010. PMC2812690
- Waxman, EA, Giasson, BI. A novel, high-efficiency cellular model of fibrillar alpha-synuclein inclusions and the examination of mutations that inhibit amyloid formation. J. Neurochem. 113, 374-388, 2010. PMC2907888
- Ramsey, CP, Giasson, BI. Identification and characterization of a novel endogenous murine parkin mutation. J. Neurochem. 113, 402-417, 2010. PMC2908247
- Ramsey, CP, Tsika, E, Ischiropoulos, H, Giasson, BI. DJ-1 deficient mice demonstrate similar vulnerable to pathogenic Ala53Thr human alpha-synuclein toxicity. Hum. Mol. Genet. 19, 1425-1437, 2010. PMC2846158
- Kuo, Y-M, Li, Z, Jiao, Y, Gaborit, N, Pani, AK, Orrison, BM, Bruneau, BG, Giasson, BI. Smeyne, R.J., Gershon, M.D., Nussbaum, R.L. Enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing human alpha-synuclein genes with Parkinson disease-associated mutations. Hum. Mol. Genet. 19, 1633-1650, 2010. PMC2850613
- Tsika, E, Moysidou, M, Guo, J, Cushman, M, Gannon, P, Sandaltzopoulos, R, Giasson, BI, Krainc, D, Ischiropoulos, H, Mazzulli, JR. Distinct regional-specific alpha-synuclein oligomers in A53T transgenic mice: implications for neurodegeneration. J. Neurosci. 30, 3409-3418, 2010. PMC2844128
- Ramsey, CP, Giasson, BI. L10P and P158DEL DJ-1 mutations cause protein instability, aggregation, and dimerization impairments. J. Neurosci. Res. 88, 3111-3124, 2010. PMC2943528
- Covy, JP, Giasson, BI. Effects of divalent cations on the kinase activity of wild-type and disease causing mutations of leucine-rich repeat kinase 2. J. Neurochem. 115, 36-46, 2010. PMC2963190
- Waxman, EA, Giasson, BI. Characterization of kinases involved in the phosphorylation of aggregated α-synuclein. J. Neurosci. Res. 89, 231-247, 2011. "PMC Journal - In Process."
- Waxman, EA, Giasson, BI. Induction of intracellular tau aggregation is promoted by alpha-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J Neurosci. 25, 7604-7618, 2011. PMC3122484
- Covy, JP, Giasson, B I. Alpha-synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of parkinson disease. Neurotoxicology In press, 2011 PMC3134594