Abstract
The autophagy-lysosomal pathway is an essential cellular mechanism that degrades aggregated proteins and damaged cellular components to maintain cellular homeostasis. Here, we identified HEXA-018, a novel compound containing a catechol derivative structure, as a novel inducer of autophagy. HEXA-018 increased the LC3-I/II ratio, which indicates activation of autophagy. Consistent with this result, HEXA-018 effectively increased the numbers of autophagosomes and autolysosomes in neuronal cells. We also found that the activation of autophagy by HEXA-018 is mediated by the AMPK-ULK1 pathway in an mTOR-independent manner. We further showed that ubiquitin proteasome system impairment- or oxidative stress-induced neurotoxicity was significantly reduced by HEXA-018 treatment. Moreover, oxidative stress-induced mitochondrial dysfunction was strongly ameliorated by HEXA-018 treatment. In addition, we investigated the efficacy of HEXA-018 in models of TDP-43 proteinopathy. HEXA-018 treatment mitigated TDP-43 toxicity in cultured neuronal cell lines and Drosophila. Our data indicate that HEXA-018 could be a new drug candidate for TDP-43-associated neurodegenerative diseases.
Highlights
The autophagy-lysosomal pathway (ALP) is an evolutionarily conserved catabolic mechanism that involves the degradation of unnecessary or abnormal proteins/organelles (Lee, 2012)
We found that HEXA-018, a novel compound containing a catechol derivative structure, activated the autophagic pathway via an mTORindependent pathway and mitigated neuronal toxicity induced by oxidative stress and ubiquitin proteasome system (UPS) impairment
We observed that HEXA-018 treatment upregulated the transcription of lc3a and lc3b mRNA in N2a cells and primary neurons (Figure 1C)
Summary
The autophagy-lysosomal pathway (ALP) is an evolutionarily conserved catabolic mechanism that involves the degradation of unnecessary or abnormal proteins/organelles (Lee, 2012). The postmitotic and long-lived nature of neurons makes them vulnerable to proteotoxic stress induced by the accumulation of misfolded proteins or damaged organelles (Son et al, 2012). Maintaining efficient ALP function is essential for neuronal survival, and dysfunction of the ALP is one of the common features of neurodegenerative diseases (Son et al, 2012). Under pathological conditions, cytoplasmic transfer of TDP-43 increases, and mislocalized TDP-43 accumulates in the cytoplasm, which could contribute to neuronal dysfunction and toxicity (Van Deerlin et al, 2008). Cytoplasmic aggregation of TDP-43 in affected neurons is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), HEXA-018 Mitigates TDP-43 Toxicity frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE) (Huang et al, 2020)
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