정윤하 (한국뇌연구원, Johns Hopkins University School of Medicine )

한빛사논문

조회1,893

한국뇌연구원, Johns Hopkins University School of Medicine

CV File 298 kb

Autophagy, Published online: 07 Jul 2019 | https://doi.org/10.1080/15548627.2019.1635379 Upregulation of ATG7 Attenuates Motor Neuron Dysfunction Associated with Depletion of TARDBP/TDP-43

Aneesh Donde^a,b,*, Mingkuan Sun^a,*, Yun Ha Jeong^a,c,*, Xinrui Wen^a, Jonathan Ling^a, Sophie Lin^a, Kerstin Braunstein^a, Shuke Nie^a, Sheng Wang^a,#, Liam Chen^a, and Philip C. Wong^a,b

^aDepartments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; ^bNeuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; ^cDepartment of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Korea

^#Current address: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201
^*These authors contributed equally to this manuscript.

CONTACT :
Liam Chen, Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
Philip C. Wong, Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Abstract

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.

KEYWORDS: ALS, ATG7, autophagy, Drosophila, frontotemporal dementia, mouse, SQSTM1/p62, TARDBP/TDP-43

논문정보

형식Research article
게재일2019년 07월 (BRIC 등록일 2019-07-11)
연구진국내+국외 연구진
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