HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells

Area of Science:

• Cellular Biology
• Neuroscience
• Pharmacology

Background:

• The autophagy-lysosomal pathway is crucial for cellular homeostasis, degrading waste proteins and damaged organelles.
• Dysfunction in this pathway is implicated in various neurodegenerative diseases.

Purpose of the Study:

• To identify novel inducers of autophagy.
• To evaluate the therapeutic potential of a novel compound, HEXA-018, in neurodegenerative disease models.

Main Methods:

• Assessed autophagy activation by measuring the LC3-I/II ratio and autophagosome/autolysosome numbers.
• Investigated the signaling pathway involved in HEXA-018-induced autophagy (AMPK-ULK1, mTOR-independent).
• Evaluated HEXA-018's neuroprotective effects against ubiquitin proteasome system impairment, oxidative stress, and TDP-43 toxicity in cellular and Drosophila models.

Main Results:

• HEXA-018 was identified as a novel autophagy inducer, increasing LC3-I/II ratio and autophagosome/autolysosome formation in neuronal cells.
• Autophagy activation by HEXA-018 is mediated via the AMPK-ULK1 pathway, independent of mTOR.
• HEXA-018 significantly reduced neurotoxicity induced by proteasome impairment and oxidative stress, and ameliorated mitochondrial dysfunction.
• HEXA-018 treatment mitigated TDP-43 toxicity in neuronal cell lines and Drosophila models.

Conclusions:

• HEXA-018 is a potent inducer of autophagy through the AMPK-ULK1 pathway.
• HEXA-018 demonstrates significant neuroprotective effects against various cellular insults relevant to neurodegeneration.
• HEXA-018 shows therapeutic potential as a drug candidate for TDP-43 proteinopathies and related neurodegenerative diseases.