Diversity Supplement for Validating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTD (Butler)

用于验证分泌性自噬作为多种形式的 ALS 和 FTD 治疗策略的多样性补充 (Butler)

• 批准号: 10303769
• 负责人: Justin Kawika Ichida
• 金额: $ 1.81万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303769
• 关键词: ALS patients; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; Autophagocytosis; Autophagosome; C9ORF72; Chemicals; Complex; Data; Dipeptides; Disease; Dose; Drosophila genus; Frontotemporal Dementia; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Human; In Vitro; Individual; Lipids; Lysosomes; Mainstreaming; Mediating; Modeling; Motor Neurons; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathway interactions; Patients; Phenotype; Phosphotransferases; Proteins; Research; System; Technology; Therapeutic; Thinking; Treatment Efficacy; Ubiquitin; Vesicle; causal variant; efficacy validation; exosome; frontotemporal lobar dementia-amyotrophic lateral sclerosis; high throughput screening; in vivo; induced pluripotent stem cell; inhibitor/antagonist; misfolded protein; motor neuron degeneration; mouse model; multicatalytic endopeptidase complex; neuron loss; new therapeutic target; novel therapeutic intervention; novel therapeutics; parent grant; presenilin-1; prevent; protein TDP-43; proteostasis; sporadic amyotrophic lateral sclerosis; superoxide dismutase 1; therapeutic target; therapeutically effective; trafficking

Project Summary/Abstract (from Parent Grant) ALS, FTD, and Alzheimer’s are complex diseases that each result from many diverse genetic etiologies. Although therapeutic strategies that target specific causal mutations (e.g. SOD1 ASOs) may prove effective against individual forms of ALS and FTD, these approaches cannot address the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that likely contribute to ALS and FTD and the fact that each genetic form is relatively rare, this strategy may be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of ALS and FTD, particularly those with unknown genetic etiologies. To identify new therapeutic targets that rescue multiple forms of ALS, we performed unbiased chemical screens to search for targets that can rescue the degeneration of iPSC motor neurons from multiple C9ORF72 and sporadic ALS patients. Inhibitors of PIKFYVE kinase were among the most potent and broadly-efficacious compounds across patient lines. Surprisingly, the data show that PIKFYVE inhibition rescues neurodegeneration by blocking autophagosome- lysosome fusion, which induces secretory autophagy to clear misfolded proteins including C9ORF72 dipeptide repeat proteins and TDP-43 through exosomal secretion. The accumulation of misfolded proteins can induce neuron death and is a common feature of neurodegenerative diseases. Although studies have sought to stimulate known proteostasis pathways including the proteosome and autophagy, these pathways decline during aging and may be difficult to rescue effectively. Intriguingly, recent studies have shown that neurons use exosomal secretion as a third proteostasis pathway. However, it remains unknown if this pathway can be harnessed to treat ALS and related neurodegenerative diseases. The central hypothesis of the proposed study that secretory autophagy is one of the most potent ways to prevent neurodegeneration in ALS, FTD, and Alzheimer’s disease differs from mainstream thinking in the field. Evaluating this hypothesis is crucial because activating the proteasome and autophagy has had mixed results in neurodegeneration models. The proposed study will 1) confirm that secretory autophagy is the therapeutic mechanism of PIKFYVE inhibition, 2) determine the efficacy of secretory autophagy in ALS, FTD, and Alzheimer’s disease patient-derived neurons, and 3) validate the efficacy of PIKFYVE suppression with antisense oligonucleotides in vivo. This application seeks to shift current research by validating the induction of secretory autophagy as a highly effective therapeutic strategy for diverse forms of ALS, FTD, and Alzheimer’s disease. The proposed study will establish PIKFYVE suppression and secretory autophagy as critical therapeutic targets for ALS and related neurodegenerative diseases. More broadly, this therapeutic strategy may be effective for other diseases driven by aberrant protein accumulation.

项目摘要/摘要（来自家长补助金）