Project Summary/Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder behind Alzheimer’s
disease, and is a major burden to society. PD is a progressive disorder resulting in a variety of symptoms
including dementia, autonomic, and motor dysfunction; all contributing to a diminished quality of life for afflicted
individuals. Current treatments help to restore motor function, however there are no disease-modifying
treatments that halt or slow the progression of PD. Deep brain stimulation (DBS) of the subthalamic nucleus
(STN) is applied with increasing frequency to treat the cardinal motor symptoms of PD. STN DBS has typically
been used as a treatment of last resort, considered only after patients no longer respond to pharmacotherapy.
As a result, the average patient undergoing STN DBS is 12-14 years post diagnosis. Post mortem studies
examining early PD subjects reveal that the overwhelming majority of putaminal denervation has already
occurred within the first 3-5 years after diagnosis. Therefore, the question of whether STN DBS can provide
neuroprotection against nigrostriatal degeneration, beyond symptomatic relief, remains to be examined in the
appropriate early stage clinical cohort. Indeed, a recent clinical pilot study has demonstrated that STN DBS in
early stage PD patients is safe and efficacious, and also suggests a disease modifying effect. Preclinical
studies by our group and others have demonstrated that STN DBS applied prior to, or following neurotoxicant
insult (MPTP, 6-OHDA) can protect against degeneration of nigrostriatal dopamine (DA) neurons in both rats
and nonhuman primates. In our laboratory we have directly linked the neuroprotective potential of STN DBS
with stimulation-induced brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase type B (trkB)
signaling in substantia nigra pars compacta (SNpc) neurons. In contrast to results in neurotoxicant models,
STN DBS applied in a-syn overexpression models has yielded mixed results with regards to neuroprotection.
Whether STN DBS can protect the nigrostriatal system in the context of synucleinopathy therefore remains an
open question. In the present proposal I will use an alternative synucleinopathy model that has been well-
characterized by our laboratory in rats to examine the question of STN DBS-mediated neuroprotection. This
model is induced by injection of pre-formed a-syn fibrils (PFF) and offers the ability to examine
synucleinopathy in the context of normal endogenous a-syn levels. Supraphysiological a-syn expression is not
analogous to a-syn levels in PD and may result in neurotoxic mechanisms unrelated to PD pathogenesis. As
such, the a-syn PFF model may be more disease-relevant than a-syn overexpression models. In Aim 1, I will
examine the impact of STN DBS on PFF-induced phosphorylated a-syn (pSyn) inclusions and BDNF-TrkB
signaling during the peak of pSyn accumulation in the SNpc. In Aim 2 I will investigate whether initiating STN
DBS following nigral pSyn accumulation provides neuroprotection. Collectively, these studies will provide
evidence to support or refute the neuroprotective potential of STN DBS against synucleinopathy.