Targeting the acetyltransferase NAT10 corrects pathologies in human frontotemporal neurons and extends lifespan in an in vivo Drosophila tauopathy model
Paonessa, F.; Bizzini, B.; Campbell, T.; Solanki, R.; Butler, R.; Smith, J.; Davidson, C.; Larrieu, D.; Brand, A.; Livesey, F.
Show abstract
Disruption of the neuronal nuclear membrane and perturbation of nucleocytoplasmic transport are features of neurodegenerative diseases, including Alzheimers disease, that involve the microtubule-associated protein tau (MAPT). We previously identified that missense and splicing mutations in the MAPT gene, causal for frontotemporal dementia, result in nuclear envelope deformation and disrupted nucleocytoplasmic transport in human neurons. This is most likely due to microtubule mechanical stress, similar to that observed in Hutchinson-Gilford Progeria Syndrome (HGPS). A small molecule inhibitor of the acetyltransferase NAT10 has been shown to correct nuclear membrane defects in HGPS by modulating microtubule dynamics. We report here that NAT10 inhibition alters microtubule dynamics and corrects nuclear lamina defects and aberrant nucleocytoplasmic transport in human iPSC-derived FTD-MAPT neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. Our results show that NAT10 mediates neuronal pathologies in tauopathies and is a promising new therapeutic target in these diseases.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Aβ-driven nuclear pore complex dysfunction alters activation of necroptosis proteins in a mouse model of Alzheimer's Disease 96%
- Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin 96%
- Exploring therapeutic strategies for Infantile Neuronal Axonal Dystrophy (INAD/PARK14) 95%
Similar papers in this journal
- Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration 96%
- HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs 95%
- A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide 94%
Similar papers in this journal
- Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease 96%
- Opposing roles of p38α phosphorylation and arginine methylation in driving TDP-43 proteinopathy. 95%
- Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy 95%
Similar papers in this journal
- Nuclear Import Defects Drive Cell Cycle Dysregulation in Neurodegeneration 95%
- S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice 93%
- The SATB1-MIR22-GBA axis mediates glucocerebroside accumulation inducing a cellular senescence-like phenotype in dopaminergic neurons 93%