Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation DOI Creative Commons
Avanti Gokhale, Hadassah Mendez-Vazquez, Maureen M. Sampson

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Abstract Manganese (Mn) is an essential trace element required for various biological functions, but excessive Mn levels are neurotoxic and lead to significant health concerns. The mechanisms underlying Mn-induced neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, neuronal loss, along with evidence neuroinflammation. Here, we present a novel Mn-dependent mechanism linking mitochondrial dysfunction We found that disrupts transcriptome processing, resulting in the accumulation complementary RNAs form double-stranded RNA (dsRNA). This dsRNA released cytoplasm, where it activates cytosolic sensor pathways, triggering type I interferon responses inflammatory cytokine production. 100-day human cerebral organoids, observed predominantly mature astrocytes. Similar effects were vivo mouse model carrying mutations SLC30A10 gene, which results accumulation. These findings highlight previously unrecognized role neuroinflammation provide insights into molecular basis manganism. propose this dsRNA-induced pathway has broad implications neurodegenerative diseases caused by environmental or genetic insults.

Язык: Английский

Mitochondrially Transcribed dsRNA Mediates Manganese-induced Neuroinflammation DOI Creative Commons
Avanti Gokhale, Hadassah Mendez-Vazquez, Maureen M. Sampson

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

Abstract Manganese (Mn) is an essential trace element required for various biological functions, but excessive Mn levels are neurotoxic and lead to significant health concerns. The mechanisms underlying Mn-induced neurotoxicity remain poorly understood. Neuropathological studies of affected brain regions reveal astrogliosis, neuronal loss, along with evidence neuroinflammation. Here, we present a novel Mn-dependent mechanism linking mitochondrial dysfunction We found that disrupts transcriptome processing, resulting in the accumulation complementary RNAs form double-stranded RNA (dsRNA). This dsRNA released cytoplasm, where it activates cytosolic sensor pathways, triggering type I interferon responses inflammatory cytokine production. 100-day human cerebral organoids, observed predominantly mature astrocytes. Similar effects were vivo mouse model carrying mutations SLC30A10 gene, which results accumulation. These findings highlight previously unrecognized role neuroinflammation provide insights into molecular basis manganism. propose this dsRNA-induced pathway has broad implications neurodegenerative diseases caused by environmental or genetic insults.

Язык: Английский

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