Batten, with an incidence as high as one in 12,500 live births. Batten disease results from mutation of CLN3, and is characterized pathologically by the accumulation of autofluorescent hydrophobic material in the lysosome of neurons and other cell types. However, the mechanism driving these cellular alterations and the manner in which they relate to the neurodegeneration in Batten disease is unknown. Individuals with Batten disease, and a cln3-knockout mouse model for Batten disease have a circulating autoantibody to glutamic acid decarboxylase (GAD65) that is inhibitory to this enzyme's ability to convert glutamic acid to 7-aminobutyric acid (GABA). The GAD65 autoantibody associates with the brain in cln3-knockout mice, inhibits the activity of GAD, and results in a subsequent elevation of glutamate and altered expression of genes involved in the regulation and utilization of glutamate. The major goal of this proposal is to establish and characterize the contribution of the GAD65 autoantibody to the pathogenesis of Batten disease. As the model for this study is a genetically defined I knockout mouse, we will establish whether the presence of a GAD65 autoantibody is simply an epiphenomenon, and whether it contributes directly to Batten disease. We shall: (i) construct cln3-knockout mice that are unable to mount an immune response to GAD65 by crossing to MuMT and C-alpha knockout mice, which lack the ability to generate B-cells, and CD4+ and CD8+ T-cells, respectively. This will enable us to determine whether the autoantibody contributes to the pathology of Batten disease. (ii) test by passive transfer of GAD65 autoantibodies to normal mice the degree of pathogenicity on the CNS mediated by these autoantibodies. Also, by transfer of GAD65 autoantibodies to immune deficient mice we will determine if the cln3-defect allows for preferential deposition of IgG in the brain (iii) define the inflammatory response to the presence of autoantibodies and the participation of the innate immune system in the disease process in cln3-knockout mice by examining cytokines such as IL-1 and TNF, complement proteins and microglial activation, respectively. (iv) characterize cell type specific molecular effects that elevated glutamate and exposure to the autoantibody have on primary neuronal culture from cln3-knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044310-04
Application #
7113816
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Tagle, Danilo A
Project Start
2003-09-15
Project End
2009-04-30
Budget Start
2006-09-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$330,741
Indirect Cost
Name
University of Rochester
Department
Biochemistry
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Cárcel-Trullols, Jaime; Kovács, Attila D; Pearce, David A (2017) Role of the Lysosomal Membrane Protein, CLN3, in the Regulation of Cathepsin D Activity. J Cell Biochem 118:3883-3890
Beraldi, Rosanna; Meyerholz, David K; Savinov, Alexei et al. (2017) Genetic ataxia telangiectasia porcine model phenocopies the multisystemic features of the human disease. Biochim Biophys Acta Mol Basis Dis 1863:2862-2870
Meyer, Meredith; Kovács, Attila D; Pearce, David A (2017) Decreased sensitivity of palmitoyl protein thioesterase 1-deficient neurons to chemical anoxia. Metab Brain Dis 32:275-279
Thada, Vaughn; Miller, Jake N; Kovács, Attila D et al. (2016) Tissue-specific variation in nonsense mutant transcript level and drug-induced read-through efficiency in the Cln1(R151X) mouse model of INCL. J Cell Mol Med 20:381-5
Hersrud, Samantha L; Kovács, Attila D; Pearce, David A (2016) Antigen presenting cell abnormalities in the Cln3(-/-) mouse model of juvenile neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1862:1324-36
Hersrud, Samantha L; Geraets, Ryan D; Weber, Krystal L et al. (2016) Plasma biomarkers for neuronal ceroid lipofuscinosis. FEBS J 283:459-71
Kovács, Attila D; Pearce, David A (2015) Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender. Dis Model Mech 8:351-61
Kovács, Attila D; Hof, Caitlin; Pearce, David A (2015) Abnormally increased surface expression of AMPA receptors in the cerebellum, cortex and striatum of Cln3(-/-) mice. Neurosci Lett 607:29-34
Miller, Jake N; Pearce, David A (2014) Nonsense-mediated decay in genetic disease: friend or foe? Mutat Res Rev Mutat Res 762:52-64
Weber, Krystal; Pearce, David A (2013) Large animal models for Batten disease: a review. J Child Neurol 28:1123-7

Showing the most recent 10 out of 45 publications