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 ?-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 ?-syn fibrils (PFF) and offers the ability to examine synucleinopathy in the context of normal endogenous ?-syn levels. Supraphysiological ?-syn expression is not analogous to ?-syn levels in PD and may result in neurotoxic mechanisms unrelated to PD pathogenesis. As such, the ?-syn PFF model may be more disease-relevant than ?-syn overexpression models.
In Aim 1, I will examine the impact of STN DBS on PFF-induced phosphorylated ?-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.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been an effective treatment for the motor symptoms of Parkinson?s disease (PD), however its potential as a disease-modifying therapy remains uncertain. Herein I propose to examine the effects of STN DBS on the formation of aggregates of a protein called alpha-synuclein, a process linked to degeneration of substantia nigra neurons, as well as the degenerative process itself. These finding, regardless of the outcome, will provide critical insight into the neuroprotective potential of STN DBS in Parkinson?s disease.
