Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: The new molecular mechanism of ibudilast and its implication for neuroprotective therapy
Abstract
A key feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease (PD) and Huntington's disease (HD) is abnormal aggregation and deposition of misfolded proteins. Previous studies have shown that autophagy plays an important role in the clearance of disease-linked protein aggregates. In the current study, we report that ibudilast, which is a non-selective inhibitor of phosphodiesterases (PDEs) and an anti-inflammation drug, can induce autophagy and lysosomal biogenesis through mammalian target of rapamycin complex 1 - transcription factor EB (mTORC1-TFEB) signaling. We have found that ibudilast significantly enhances the clearance of disease-linked TAR DNA binding protein (TDP-43) and superoxide dismutase 1 (SOD1) protein aggregates in transfected cellular models carrying corresponding gene mutations. The mechanistic study revealed that ibudilast could markedly enhance TFEB nuclear translocation and increase the autolysosomes by inhibiting mTORC1 activity. We have also demonstrated that ibudilast could protect TDP-43-induced cytotoxicity in motor neuron-like NSC-34 cells. Collectively, our study identifies ibudilast as an autophagy enhancer and provides insights into the molecular basis of ibudilast for the potential treatment of several neurodegenerative disorders.
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Ibudilast induces autophagy by promoting TFEB activity, which enhances clearance of TARDBP aggregates and reduces cytotoxicity.
“the phosphodiesterase inhibitor ibudilast induces autophagy by promoting TFEB activity, which enhances clearance of TARDBP aggregates and reduces cytotoxicity [360].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [360]
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Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
“phosphodiesterase inhibitor ibudilast induces autophagy by promoting TFEB activity, which enhances clearance of TARDBP aggregates and reduces cytotoxicity [360].”
Background
- Authors
- Chen, Y., Wang, H., Ying, Z., & Gao, Q.
- Affiliations
- Tianjin University (CN)
- Soochow University (CN)
- Corresponding author
- Ying, Zheng
- Gao, Qingzhi
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 526
- Issue
- 1
- Pages
- 231-238
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W3012688546
- Cited by
- 63
- References
- 44
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 14 · 2021: 14 · 2020: 5
- FWCI
- 4.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- ibudilast, TDP-43 aggregates, autophagy, lysosomal biogenesis, TFEB, mTORC1, protein aggregate clearance, neurodegenerative diseases, amyotrophic lateral sclerosis, neuroprotection, phosphodiesterase inhibitors, motor neuron toxicity
- MeSH terms
- Neuroprotection, Autophagosomes, Superoxide Dismutase-1, Mechanistic Target of Rapamycin Complex 1, Amyotrophic Lateral Sclerosis, Autophagy, Cell Nucleus, DNA-Binding Proteins, Humans, Indolizines, Lysosomes, Membrane Fusion, Pyrazoles, Pyridines, Cell Death, Neuroprotective Agents, Protein Transport, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, HEK293 Cells, Protein Aggregates
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