STN DBS Effects on Neuroinflammation and Degeneration Induced by Alpha-Synuclein Inclusions

项目总结

Project Summary Subthalamic nucleus deep brain stimulation (STN DBS) to treat the cardinal motor symptoms of Parkinson’s disease (PD) has increased dramatically since its first use was reported in 1994. DBS is a vetted, safe and efficacious neurosurgical therapy for PD. Once considered a treatment of last-resort with patients undergoing neurosurgery approximately 10-16 years post diagnosis, STN DBS now is FDA approved for use as early as four years after diagnosis and symptomatic efficacy may be superior to medical therapy at that time. Questions remain as to whom will best benefit from additional and earlier years of stimulation treatment. Specifically, the question of whether early STN DBS can modify the progression of PD has yet to be examined in an appropriately designed clinical trial. Dopaminergic denervation of the putamen is nearly complete within four years of PD diagnosis and precedes loss of nigral neurons. Thus, neuroprotective therapies that seek to protect the nigrostriatal system cannot be adequately evaluated in subjects with disease duration longer than this four-year timeframe. Several clinical studies have investigated whether STN DBS has the ability to slow or halt the progression of PD. However, the common thread in all of these studies is that the subjects enrolled were mid to late-stage PD when STN DBS was initiated. Most recently, a pilot trial has shown that STN DBS was applied within 2 years of PD diagnosis is safe and efficacious with subjects receiving STN DBS exhibiting a slower worsening of rest tremor. This suggests that early DBS may slow some aspects of PD progression. Preclinical studies by our group and others have demonstrated that STN DBS can protect against degeneration of nigrostriatal dopamine (DA) neurons induced by neurotoxicant insult in both rats and nonhuman primates. In our laboratory we have previously shown that STN DBS significantly increases brain- derived neurotrophic factor (BDNF) in the nigrostriatal system and the primary motor cortex (M1). Further, we have directly linked the neuroprotective effect of STN DBS to BDNF-tropomyosin receptor kinase type B (trkB) signaling in substantia nigra pars compacta (SNpc) neurons as trkB blockade prevents this neuroprotection. In contrast to results in neurotoxicant models, STN DBS applied in the alpha-synuclein (α-syn) overexpression models has yielded mixed neuroprotection results. Whether STN DBS can protect the nigrostriatal system in the context of synucleinopathy therefore remains an open question. In the present proposal we employ an alternative synucleinopathy model: the α-syn preformed fibril (PFF) model. The α-syn PFF model shares key features of idiopathic PD and may be more disease-relevant to idiopathic PD than α-syn overexpression models, potentially providing greater predictive validity. Using the α-syn PFF model we will determine whether STN DBS can provide neuroprotection of SNpc cell bodies, SNpc nigrostriatal terminals and M1 corticostriatal neurons. We will further investigate the impact of long-term STN DBS on potential arbiters of neuroprotection and disease-modification: neuroinflammation and BDNF.