The Establishment of a Pre-Clinical Model for Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) has a myriad of symptoms, the most visible being difficulties in motor function. There are less obvious deficits, such as cognitive impairment and a reduction in the startle reflex to loud acoustic stimuli (ASR). The latter phenomenon may distinguish PSP from other forms of Parkinson’s disease (PD). ASR is modulated by brainstem structures, principally the pedunculopontine tegmentum (PPTg), which is seen to be degenerated in both PD and PSP.

However, while the degeneration of the PPTg in PD is non-selective to the type of neuron, in PSP it is seen to be a more selective to the cholinergic neurons. The investigator has engineered a method to mimic the unique loss of cholinergic neurons seen in PSP. When used in rats, there are motor deficits and a reduction in ASR.

This project will study the long-term impact of the selective ablation of PPTg cholinergic neurons to determine what other PSP symptomology could be due to the loss of PPTg cholinergic neurons. Another feature that distinguishes PSP from PD is the presence of tau protein aggregates and tangles throughout the brain. These brain regions are known to receive neural inputs from the PPTg.

Therefore, this study will selectively overexpress tau protein in the cholinergic neurons of the PPTg. This will likely recapitulate PSP in a number of ways: deposit Tau in the same brain regions; result in the selective death of the cholinergic neurons;  produce analogous behavioral symptomology (e.g., deficits in acoustic startle and motor deficits); and produce a model with a slow onset of symptoms. These animal models are the first steps towards drug discovery for PSP and will allow for improved diagnosis, identification of effective drugs and the study of the degeneration and histopathology that is unique to PSP.

RESULTS: Progressive Supranuclear Palsy (PSP) has a myriad of symptoms, the most visible being difficulties in motor function. There are less obvious deficits, such as cognitive impairment and a reduction in the startle reflex to loud acoustic stimuli (ASR). The latter phenomenon may distinguish PSP from other forms of Parkinson’s Disease (PD). ASR is modulated by brainstem structures, principally the pedunculopontine tegmentum (PPTg), which is seen to be degenerated in both PD and PSP. However, while the degeneration of the PPTg in PD is non-selective to the type of neuron, in PSP it is a more extensive and selective loss of the cholinergic neurons. Recently we have engineered a method to mimic the unique loss of cholinergic neurons seen in PSP. When used in rats to remove the cholinergic neurons, there are motor deficits and a reduction in ASR. Therefore, we proposed to study the long-term impact of the selective remomval of PPTg cholinergic neurons, to determine what other PSP symptomology could be due to the loss of PPTg cholinergic neurons.

After selective cholinergic PPTg removal (lesioned), we allowed the animals to live for over a year and compared behavioral and postmortem pathology of lesioned to sham-operated rats. The lesion-induced deficit in ASR never improved and motor deficits worsened over the course of the year. These deficits included an increase in the number of “slips” while navigating various beams and poorly coordinated transitions from an elevated platform into homecages. Histological analysis discovered that the loss of cholinergic PPTg neurons precipitated a significant loss of substantia nigra dopamine neurons (35%) and a significant enlargement of the lateral ventricles (~100% increase). While the former is seen in both PD and PSP, the latter is a distinguishing feature between PSP and PD. To our knowledge, this is the first preclinical model of PSP that encompasses many relevant behavioral (4) and neuropathological (3) features.

Another feature that distinguishes PSP from PD is the presence of Tau protein aggregates and tangles throughout the brain. The brain regions impacted in PSP are known to receive neural inputs from the PPTg. Therefore, we have established a method to selectively overexpress Tau protein in the cholinergic neurons of the PPTg. This will recapitulate PSP in the same ways as the lesion (above) due to the Tau selectively killing the cholinergic PPTg neurons, but with the added feature of depositing Tau in the same brain regions as seen in PSP afflicted brains.

These two animal models (cholinergic PPTg lesion and Tau overexpression) are the first steps towards drug discovery for PSP and will allow for: 1) improved diagnosis, 2) identification of effective drugs, and 3) the study of the degeneration and histopathology that is unique to PSP.