Carbon disulfide induces accumulation of TDP-43 in the cytoplasm and mitochondrial dysfunction in rat spinal cords.
Cereb Cortex
; 34(2)2024 01 31.
Article
in En
| MEDLINE
| ID: mdl-38185999
ABSTRACT
The relationship between environmental neurotoxicant exposure and neurodegenerative diseases is being extensively investigated. Carbon disulfide, a classic neurotoxicant and prototype of dithiocarbamates fungicides and anti-inflammatory agents, has been detected in urban adults, raising questions about whether exposure to carbon disulfide is associated with a high incidence of neurodegenerative diseases. Here, using rat models and SH-SY5Y cells, we investigated the possible mechanistic linkages between carbon disulfide neurotoxicity and the expression of TDP-43 protein, a marker of amyotrophic lateral sclerosis/frontotemporal lobar degeneration. Our results showed that rats exhibited severe dyskinesia and increased TDP-43 expression in the spinal cord following carbon disulfide exposure. Moreover, carbon disulfide exposure induced abnormal cytoplasmic localization and phosphorylation of TDP-43 in motor neurons. Importantly, carbon disulfide treatment led to the accumulation of TDP-43 in the mitochondria of motor neurons and resulted in subsequent mitochondrial damage, including mitochondrial structural disruption, mitochondrial respiratory chain complex I inhibition, and impaired VCP/p97-dependent mitophagy. In summary, our study provides support for carbon disulfide exposure-mediated TDP-43 mislocalization and mitochondrial dysfunction, contributes to understanding the pathogenesis of environmental neurotoxin-induced neurodegeneration, and provides inspiration for potential therapeutic strategies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carbon Disulfide
/
Neurodegenerative Diseases
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Mitochondrial Diseases
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Amyotrophic Lateral Sclerosis
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Neuroblastoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Cereb Cortex
Journal subject:
CEREBRO
Year:
2024
Document type:
Article
Affiliation country: