Mutation ∆K281 in MAPT causes Pick's disease.

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Frontotemporal dementia (FTD) is a group of progressive neurodegenerative disorders.
• Mutations in the MAPT gene are known causes of FTD.
• Tau pathology is a hallmark of many neurodegenerative diseases, including FTD and Pick's disease.

Purpose of the Study:

• To investigate the clinicopathological features of frontotemporal dementia in siblings with a novel MAPT deletion mutation (∆K281).
• To characterize the specific tau protein aggregation and filament structure in the affected brain tissue.
• To determine the relationship between the MAPT ∆K281 mutation and the observed neuropathology.

Main Methods:

• Autopsy examination of brain tissue from affected siblings.
• Histopathological staining using various silver stains and antibodies against tau protein.
• Biochemical characterization of tau inclusions using luminescent conjugated oligothiophenes (HS-84 and bTVBT4).
• Electron cryo-microscopy for ultrastructural analysis of tau filaments.

Main Results:

• Siblings presented with frontotemporal dementia.
• Brain autopsy revealed widespread hyperphosphorylated 3R tau inclusions in neurons and glial cells.
• Inclusions were argyrophilic with Bodian silver but not Gallyas-Braak silver.
• Inclusions did not react with antibodies specific for tau phosphorylated at S262/S356.
• HS-84 stained the inclusions, while bTVBT4 did not.
• Electron cryo-microscopy showed tau filaments with a core structure (K254-F378 of 3R Tau) identical to Pick's disease.

Conclusions:

• The MAPT mutation ∆K281 is associated with frontotemporal dementia.
• The observed tau pathology, characterized by specific biochemical and ultrastructural features, is indistinguishable from that seen in Pick's disease.
• This study concludes that the MAPT mutation ∆K281 causes Pick's disease.