Summary
Progressive Supranuclear Palsy (PSP) is a debilitating disease with aggregates of tau protein in multiple brain
areas and severe mental and motor deficits. PSP is often misdiagnosed as Parkinson's Disease (rate of 50%)
and there are no drugs that help PSP sufferers. Those with PSP have a life expectancy of only 6-8 years,
suggestive that the neurodegeneration is already far advanced when symptomology becomes evident.
Therefore, there is a need to i) increase the accuracy of diagnosis, ii) find biomarkers or behavioral deficits that
predate the symptoms, and iii) find therapeutics. To facilitate these goals, we need to understand 1) from
where within the brain does the disease originate, 2) which neural pathways when degenerated produce which
symptoms, and 3) the topographical progression of pathogenesis. Based on strong preliminary data, we
propose that the accumulation of tau protein in cholinergic pedunculopontine tegmentum (PPT) neurons in the
hindbrain will produce tau aggregates in brain regions impacted in PSP, progress from a disease-free state to
a PSP-like end stage, and produce PSP-like behavioral deficits (e.g. dysexecutive frontal syndrome and motor
deficits).
To produce PSP-like pathology in rats we use a genetically engineered virus to selectively over-express the
isoform of the tau protein that predominates in PSP (1N4R) in cholinergic PPT neurons. At 5 months post-
infection, the model is consistent with PSP: i) a loss of cholinergic neurons, ii) loss of substantia nigra
dopaminergic neurons, iii) increased number of hyperphosphorylated tau-positive neurons, iv) acoustic startle
reflex deficit, and v) motor deficits. Animals with tau protein over-expression will be compared to those that
have the over-expression of a benign protein at 5 month intervals until old age. We will complete extensive
postmortem histochemical analysis, Magnetic Resonance Imaging (MRI), REM sleep recordings, and
behavioral testing (e.g. cognitive & motor) to establish whether the pathology progresses to a condition
consistent with late-stage PSP.
Once it is established that accumulation of tau in the cholinergic PPT neurons is sufficient to produce late
stage PSP-like pathology and behavior deficits, future work would include: 1) identifying strategies that
ameliorate symptomology and disease progression, 2) the discovery of early markers of disease onset, and 3)
molecular mechanistic studies (e.g. knockdown of specific targets).
