Recently, mutations in the tau gene have been linked to several neurodegenerative disorders.  In each of these cases, there was an increase of tau pathology in the frontal regions of the brain.  Although these diseases differ in the morphology of the tau filaments formed and in the precise brain regions in which they form, they have been loosely classified as frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17).  All of these diseases exhibit tau pathology in the absence of other classical pathological structures such as the b-amyloid deposits known as senile plaques.  These diseases provide genetic evidence that tau is directly involved in the neurodegenerative process.

We therefore sought to model these changes in our in vitro polymerization assay.  The mutations we investigated were:

• A Proline to Leucine change at position 301 (P301L)
• An Arginine to Tryptophan change at position 406 (R406W)
• A Valine to Methionine change at position 337 (V337M)
• A Glycine to Valine change at position 272 (G272V)

Each of these mutations caused an increase in the rate of tau polymerization, the extent of tau polymerization, or both in our in vitro assay:

Therefore, the mutations in the tau gene can lead to increased tau polymerization, and this polymerization might be a toxic gain of function.  In other words, the tau mutations might lead directly to neurodegeneration by enhancing polymer formation.

For more information, see Reference 3.