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Fibrillation and molecular characteristics are coherent with clinical and pathological features of 4-repeat tauopathy

Alexander Sandberg1, Helen Ling2, Marla Gearing3

  • 1Department of Physics Chemistry and Biology, Linköping University, Linköping, Sweden.

Neurobiology of Disease
|September 22, 2020
PubMed

Insights

The G273R tau mutation promotes the aggregation of 4-repeat tau, a key factor in tauopathies like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). This mutation alters tau

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Microtubule Associated Protein Tau (MAPT) aggregates in neurodegenerative diseases.
  • The G273R tau mutation was identified in a patient with dementia and parkinsonism.
  • Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) are characterized by 4-repeat (4R) tau aggregates.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the G273R tau mutation's role in tauopathies.
  • To characterize the in vitro and in vivo effects of the G273R mutation on tau aggregation and binding properties.

Main Methods:

  • Exome sequencing identified the G273R mutation.
  • Pathological examination of patient brain tissue.
  • Molecular biophysics studies in vitro.
  • Drosophila models were used to study tau aggregation and seeding.

Main Results:

  • The G273R mutation increases 4R tau aggregation propensity.
  • Altered binding affinity of tau to microtubules (MTs) and F-actin.
  • The mutation promotes 4R tau fibrillation in vitro and in glial cells.
  • Preferential seeding of 4R tau aggregates was observed.

Conclusions:

  • The G273R mutation contributes to 4R tauopathy by altering tau's interaction with MTs and F-actin.
  • This mutation may cause late-onset tauopathies resembling PSP and CBD.
  • Understanding these mechanisms could inform therapeutic strategies for tauopathies.
Keywords:
4-repeat tauAggregation propensityCBDCorticobasal degenerationG273RMAPTPSPPathologyProgressive supranuclear palsyTauopathy

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