Batten disease, a childhood neurodegenerative disorder results from mutations in CLN3. Patients with Batten disease and a cln3-knockout mouse have autoantibodies to several proteins including GAD65. Moreover, these autoantibodies have been shown to associate to the brain in post-mortem Batten disease tissue and in the brain of cln3-knockout mice. In the previous cycle of this grant we had proposed to establish that the autoimmune component contributed to the pathogenesis of Batten disease. In the progress report we detail publications and preliminary data that confirm a neuroimmune component to the pathogenesis of Batten disease. In addition, completion of the main aim of the original proposal, namely construction of cln3 knockout mice that are also homozygous for deletion of MuMT (the immunoglobulin mu chain) or C-alpha-mice (the alpha chain of the T-cell receptor) so they therefore lack the ability to generate B-cells, and CD4+ and CD8+ T- cells, respectively, confirms an amelioration of deteriorating motor coordination resulting from mutation of CLN3. The goal of this competitive renewal is to more specifically identify the components of the autoimmune response that contribute to the pathogenesis of Batten disease. Having established that genetic suppression of the immune system slows disease progression, we will establish whether drug mediated immune suppression using a drug that is tolerable to children can slow progression of disease. Finally, we present published and preliminary data that the novel anti-GAD65 response forms a part of a wider autoimmune response. We will therefore identify the multiple autoantigens in Batten disease to gain a greater understanding of how the autoimmune response imparts its effect on neuronal function and to develop further targets for treatment strategies. We shall (i) 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-a, complement proteins and microglial activation, respectively. (ii) We will treat cln3-knockout and control mice with immunosuppressant Mycophenolate Mofetil (CellCept) that is suitable for children, and could provide the foundation for a treatment for Batten disease. Finally we will identify additional autoantigens in batten disease by proteomic approaches. This work may lead to treatment strategies for the fatal disorder, Batten disease. Moreover, the described approach may be applied to other rare genetically inherited disorders.

Public Health Relevance

The proposed research is relevant and significant as it has the potential to increase our understanding of Batten's Disease and ultimately impact therapeutic strategies for this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Developmental Brain Disorders Study Section (DBD)
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Tagle, Danilo A
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Sanford Research/Usd
Sioux Falls
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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; 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
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
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

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