Upregulation of ATG7 attenuates motor neuron dysfunction associated with depletion of TARDBP/TDP-43
Autor: | Kerstin E. Braunstein, Xinrui Wen, Aneesh Donde, Jonathan P. Ling, Mingkuan Sun, Sheng Wang, Sophie Z. Lin, Liam Chen, Yun Ha Jeong, Shuke Nie, Philip C. Wong |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Mice Transgenic Biology TARDBP Autophagy-Related Protein 7 03 medical and health sciences Tar (tobacco residue) Downregulation and upregulation mental disorders medicine Autophagy Animals Humans Amyotrophic lateral sclerosis Molecular Biology Motor Neurons 030102 biochemistry & molecular biology nutritional and metabolic diseases Brain Cell Biology Motor neuron medicine.disease nervous system diseases Cell biology Up-Regulation DNA-Binding Proteins 030104 developmental biology medicine.anatomical_structure Cytoplasm Frontotemporal dementia Research Paper |
Zdroj: | Autophagy |
Popis: | A shared neuropathological hallmark in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is nuclear clearance and cytoplasmic aggregation of TARDBP/TDP-43 (TAR DNA binding protein). We previously showed that the ability of TARDBP to repress nonconserved cryptic exons was impaired in brains of patients with ALS and FTD, suggesting that its nuclear depletion contributes to neurodegeneration. However, the critical pathways impacted by the failure to repress cryptic exons that may contribute to neurodegeneration remain undefined. Here, we report that transcriptome analysis of TARDBP-deficient neurons revealed downregulation of ATG7, a critical gene required for macroautophagy/autophagy. Mouse and Drosophila models lacking TARDBP/TBPH in motor neurons exhibiting age-dependent neurodegeneration and motor deficits showed reduction of ATG7 and accumulation of SQSTM1/p62 inclusions. Importantly, genetic upregulation of the autophagy pathway improved motor function and survival in TBPH-deficient flies. Together with our observation that ATG7 is reduced in ALS-FTD brain tissues, these findings identify the autophagy pathway as one key effector of nuclear depletion of TARDBP that contributes to neurodegeneration. We thus suggest that the autophagy pathway is a therapeutic target for ALS-FTD and other disorders exhibiting TARDBP pathology. Abbreviations: ALS: amyotrophic lateral sclerosis; ANOVA: analysis of variance; ChAT: choline acetyltransferase; CTSD: cathepsin D; FTD: frontotemporal dementia; LAMP1: lysosomal associated membrane protein 1; NMJ: neuromuscular junction; RBFOX3/NeuN: RNA binding fox-1 homolog 3; SQSTM1: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein 43. |
Databáze: | OpenAIRE |
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