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.
Bibliographical noteFunding Information:
This work was supported by the Evelyn F. McKnight Brain Research Foundation [Memory & Cognitive Disorders Award]; National Institute of Neurological Disorders and Stroke [R01 NS40014]; Robert Packard Center for ALS Research, Johns Hopkins University [Robert Packared Center for ALS grant]; U.S. Department of Defense [AL100078]. We thank Olga Pletnikova and Juan Troncoso at Johns Hopkins Brain Resource Center for helping retrieving the postmortem ALS-FTD tissue. We thank V. Nehus and the NINDS Multiphoton Imaging Core (NS050274) for technical assistance. Camk2a-Cre and CamK-Cre ER mice were gifts of P. Worley (Johns Hopkins Univ.). This work was supported in part by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2014R1A1A1038326) to Y.H.J., the Robert Packard Center for ALS Research and McKnight Foundation to L.C. and P.C.W., the National Institute of Neurological Disorder and Stroke Grant R01 NS40014, Department of Defense Grant AL100078 and the Johns Hopkins Neuropathology Gift Fund to P.C.W.
- frontotemporal dementia
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, N.I.H., Extramural