Details

Autor(en) / Beteiligte

• Jadhav, Vaishnavi S.
• Stair, Jade G.
• Eck, Randall J.
• Smukowski, Samuel N.
• Currey, Heather N.
• Toscano, Laura Garcia
• Hincks, Joshua C.
• Latimer, Caitlin S.
• Valdmanis, Paul N.
• Kraemer, Brian C.
• Liachko, Nicole F.

Titel

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominance and reveals potential modulating targets

Ist Teil von

• Neurobiology of disease, 2024-04, Vol.193, p.106441-106441, Article 106441

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Alzheimer's disease (AD), the most common aging-associated neurodegenerative dementia disorder, is defined by the presence of amyloid beta (Aβ) and tau aggregates in the brain. However, more than half of patients also exhibit aggregates of the protein TDP-43 as a secondary pathology. The presence of TDP-43 pathology in AD is associated with increased tau neuropathology and worsened clinical outcomes in AD patients. Using C. elegans models of mixed pathology in AD, we have previously shown that TDP-43 specifically synergizes with tau but not Aβ, resulting in enhanced neuronal dysfunction, selective neurodegeneration, and increased accumulation of pathological tau. However, cellular responses to co-morbid tau and TDP-43 preceding neurodegeneration have not been characterized. In this study, we evaluate transcriptomic changes at time-points preceding frank neuronal loss using a C. elegans model of tau and TDP-43 co-expression (tau-TDP-43 Tg). We find significant differential expression and exon usage in genes enriched in multiple pathways including lipid metabolism and lysosomal degradation. We note that early changes in tau-TDP-43 Tg resemble changes with tau alone, but a unique expression signature emerges during aging. We test loss-of-function mutations in a subset of tau and TDP-43 responsive genes, identifying new modifiers of neurotoxicity. Characterizing early cellular responses to tau and TDP-43 co-pathology is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP-43 in AD. •Transcriptomic changes in C. elegans co-expressing human tau and TDP-43.•Early disease associated gene expression differences driven by tau.•Aging-emergent unique gene expression signature with co-expressed tau and TDP-43.•Gene ontology pathway analyses implicate altered lysosomes and lipid metabolism.•Mutation of differentially expressed genes finds novel modifiers of tau and TDP-43.