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15.01.19 Dementia mediated by tau mutations shows abnormalities in nuclear membranes

last modified Jan 17, 2019 08:59 AM
Livesey and Jackson lab collaboration shows that mutations in tau protein underlying frontotemporal dementia result in nuclear membrane dysfunction in neurons, with disrupted nucleo-cytoplasmic transport
15.01.19 Dementia mediated by tau mutations shows abnormalities in nuclear membranes

Mislocalized tau in the neuronal cell body leads to abnormal microtubule movements

Microtubules Deform the Nuclear Membrane and Disrupt Nucleocytoplasmic Transport in Tau-Mediated Frontotemporal Dementia

Paonessa F et al. (2019) Cell Reports 26 (3): P582-593.E5.

DOI: 10.1016/j.celrep.2018.12.085

 

Highlights from the paper

  • Tau mutations cause microtubule-mediated deformation of the nucleus in dementia
  • Nuclear deformation results in defective nucleocytoplasmic transport
  • Neuronal nuclei are deformed in the post-mortem frontotemporal dementia brain
  • Disrupted nucleocytoplasmic transport is shared in multiple dementias

 

Summary from the paper

The neuronal microtubule-associated protein tau, MAPT, is central to the pathogenesis of many dementias. Autosomal-dominant mutations in MAPT cause inherited frontotemporal dementia (FTD), but the underlying pathogenic mechanisms are unclear.

Using human stem cell models of FTD due to MAPT mutations, we find that tau becomes hyperphosphorylated and mislocalizes to cell bodies and dendrites in cortical neurons, recapitulating a key early event in FTD. Mislocalized tau in the cell body leads to abnormal microtubule movements in FTD-MAPT neurons that grossly deform the nuclear membrane. This results in defective nucleocytoplasmic transport, which is corrected by microtubule depolymerization.

Neurons in the post-mortem human FTD-MAPT cortex have a high incidence of nuclear invaginations, indicating that tau-mediated nuclear membrane dysfunction is an important pathogenic process in FTD. Defects in nucleocytoplasmic transport in FTD point to important commonalities in the pathogenic mechanisms of tau-mediated dementias and ALS-FTD due to TDP-43 and C9orf72 mutations.

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Read more about research in the Livesey lab.

 

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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