Inhibiting pathological TDP-43 phosphorylation as a therapeutic strategy for ALS

抑制病理性 TDP-43 磷酸化作为 ALS 的治疗策略

• 批准号: 9348132
• 负责人: Brian C. Kraemer
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348132
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Biological Assay; Body Weight; Brain; Cell model; Cessation of life; Clinical Trials; Cultured Cells; Deposition; Detergents; Development; Disease; Drug Targeting; Evaluation; Exhibits; Familial Amyotrophic Lateral Sclerosis; Family; Future; Genes; Genetic; Goals; Human; Knock-out; Knockout Mice; Lesion; Mediating; Modeling; Molecular; Motor; Motor Cortex; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Nerve Degeneration; Neurons; Onset of illness; Pathogenicity; Pathologic; Pathology; Patients; Penetrance; Penetration; Phosphorylation; Phosphotransferases; Proteins; Research; Role; Serine; Spinal Cord; Structure-Activity Relationship; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenes; Transgenic Model; Validation; Veterans; Work; disability; disorder subtype; drug development; drug discovery; inhibitor/antagonist; kinase inhibitor; middle age; mortality; motor neuron degeneration; mouse model; neuron loss; neuropathology; neurotoxic; neurotoxicity; pre-clinical; premature; prevent; protein TDP-43; targeted treatment; tau-tubulin kinase; therapeutic candidate; therapeutic target; tool; virtual

TAR DNA-binding protein 43 kDa (TDP-43) is the major aggregating disease protein in amyotrophic lateral sclerosis (ALS). Over 90% of ALS cases exhibit pathological lesions containing detergent insoluble deposits of phosphorylated, truncated, and ubiquitinated TDP-43 protein. TDP-43 phosphorylated at S409/410 (pS409/410) is the most consistent, robust, and specific neuropathological feature of ALS suggesting a phosphorylated TDP-43 (pTDP) mediated cascade of neurotoxicity. Furthermore pTDP has been shown to influence the aggregation of TDP-43 in cultured cells and in human ALS cases. Our previous work demonstrated pS409/410 TDP-43 mediates motor neuron toxicity of familial ALS-causing TDP-43 mutations. Kinases regulating TDP-43 phosphorylation present an attractive target for therapeutic intervention in ALS. We have identified a well-conserved TDP-43- active kinase with translational potential known as tau tubulin kinase 1 (TTBK1). Identification of brain penetrant TTBK1 inhibitors may ultimately provide a viable drug development strategy. We hypothesize that increased TDP-43 phosphorylation drives motor neuron degeneration in ALS and that blocking pTDP accumulation by inhibiting TTBK1 will protect against TDP-43 mediated neurodegeneration in ALS. Three integrated specific aims are proposed: 1) Identification of TTBK1 selective kinase inhibitors. 2) Optimization of TTBK1 selective inhibitors and validation of selective compounds in a cellular model of pTDP accumulation. 3) Validation of the role of TTBK1 in the formation of pTDP using TTBK1 knockout mice and an existing transgenic model of TDP-43 proteinopathy. The studies proposed here will set the stage for development of TTBK1 selective inhibitors as a candidate therapeutic approach for ALS.

TAR dna结合蛋白43 kDa （TDP-43）是肌萎缩症的主要聚集性疾病蛋白